Case#: PD, 44 years, female

CasePresentingHPOsFreeText: apo-B plasma levels <5% of normal; total cholesterol 2.57 (normal range 4-6.5 mmol/l), triglyceride 0.59 (normal range 0.3-1.8 mmol/l), apoB 17 (normal range 60-140 mg/dl).

CasePreviousTesting: On Western blot a truncated species of apo-B was found in the VLDL/chylomicron fraction (fig. 3), predicted based on size to be at the 5’ end of exon 26. The protein was absent from the HDL or infranate fractions.

CaseGenotypingMethod: Genomic DNA was digested with a panel of restriction enzymes and Southern blotted. Based on truncated apoB size (detected on Western blot), the variant was predicted to be at the end of exon 26. Approximately 1.7 kb of genomic DNA including exon 26 was amplified by the polymerase chain reaction (PCR), cloned into M13, and sequenced.

Variant: NM_000384.3(APOB):c.5463del (p.His1822fs), heterozygous

ClinVar: 17882

gnomAD: 0.000008797 (European non-Finnish)

Case: CP, 37 years, female

CasePresentingHPOs: HP:0003563 (reduced LDL-cholesterol level)

CasePresentingHPOsFreeText:* Plasma cholesterol and triglyceride levels for CP were below the 5th percentile; total cholesterol 2.61 (normal range 4-6.5 mmol/l), triglyceride 0.36 (normal range 0.3-1.8 mmol/l), apoB 9 (normal range 60-140 mg/dl, on Vitamin E supplement.

PresentingNotHPOs: HP:0001927 (acanthocytosis)

CaseGenotypingMethod: Genomic DNA was digested with a panel of restriction enzymes and Southern blotted. CP was heterozygous for a loss of a TaqI restriction site change which was localized to exon 25 by the hybridization pattern on Southern blot. ChP, her son, was also heterozygous. Genomic DNA in that region was amplified by the polymerase chain reaction (PCR), cloned, and sequenced.

Variant: NM_000384.3(APOB):c.3997C>T (p.Arg1333Ter), heterozygous

ClinVar: 17883

gnomAD: Not in gnomAD

CaseAddInfo: Patient is the mother of ChP who is under investigation for fat malabsorption. ChP is heterozygous for the variant c.3997C>T (p.Arg1333Ter). No abnormal i.e. truncated apoB was detected on Western blot of protein from VLDL/chylomicron, LDL, HDL or infranate fractions for CP.

Case#: DD, 21 years, female

CasePresentingHPOsFreeText: apo-B plasma levels <2% of normal and > 50% acanthocytes; total cholesterol 1.27 (normal range 4-6.5 mmol/l), triglyceride 0.3 (normal range 0.3-1.8 mmol/l), apoB 1.5 (normal range 60-140 mg/dl), “virtually no LDL”; diagnosed with “homozygous” (i.e. biallelic) familial hypobetalipoproteinemia because both parents (AD and PD) had total plasma cholesterol and apo-B levels below the 5th percentile. Designated as the proband in the paper. However, only one variant identified (note that full gene sequencing was not performed”), and therefore PD (mother of DD) was added as the proband here as she is heterozygous for the variant and has lipid levels consistent with this.

PresentingNotHPOsFreeText: No neurological or retinal disease.

CasePreviousTesting: On Western blot a truncated species of apo-B was found in the VLDL/chylomicron fraction (fig. 3), predicted based on size to be at the 5’ end of exon 26. The protein was absent from the HDL or infranate fractions.

CaseGenotypingMethod: Genomic DNA was digested with a panel of restriction enzymes and Southern blotted. Based on truncated apoB size (detected on Western blot), the variant was predicted to be at the end of exon 26. Approximately 1.7 kb of genomic DNA including exon 26 was amplified by the polymerase chain reaction (PCR), cloned into M13, and sequenced.

Variant: Variant 1: NM_000384.3(APOB):c.5463del (p.His1822fs)

ClinVar: Variant 1 17882 Variant 2 – Not identified (not that full gene sequencing was not performed)

gnomAD: Variant 1 - 0.000008797 (European non-Finnish) Variant 2 – Not identified ((not that full gene sequencing was not performed)

CaseAddInfo: PD (mother) had the truncated apo-B (apo-B39) in both her VLDL and LDL lipoprotein fractions, but it was present at reduced levels compared to the apo-B100 arising from her one normal apo-B allele (fig. 3). Only apo-B100 and apo-B48 were detected in the father, AD.

Case# B16, female, 30

CasePresentingHPOs HP:0003124 Hypercholesterolemia

CasePreviousTesting The APOB domains, including amino acids 2955–3092 and amino acids 3303–3492, were analysed in the 600 molecularly undefined ADH cases by direct Sanger sequencing

CaseMethod1 as mentioned

CaseMethod2 as mentioned

CaseGenotypingMethod Exome sequencing

Variant NM_000384.2(APOB):c.10182G>T (p.Lys3394Asn)

ClinVar 438310

gnomAD n/a

VariantEvidence Deficient LDL uptake (fig. 2).

eLOD Family A-2.7, Family B-1.8

Variant Family A- NM_000384.2(APOB):c.9175C>T (p.Arg3059Cys) Family B-NM_000384.2(APOB):c.10182G>T (p.Lys3394Asn)

ClinVar A-69508, B-438310

CAID A-CA066337, B-CA345987169

gnomAD A-0.00003249 link B-n/a

Case# A13, male, 7

CasePresentingHPOs HP:0003124 Hypercholesterolemia

CasePreviousTesting The APOB domains, including amino acids 2955–3092 and amino acids 3303–3492, were analysed in the 600 molecularly undefined ADH cases by direct Sanger sequencing

CaseMethod1 as mentioned

CaseMethod2 as mentioned

CaseGenotypingMethod Exome sequencing

Variant NM_000384.2(APOB):c.9175C>T (p.Arg3059Cys)

ClinVar 69508

gnomAD 0.00003249 link

VariantEvidence Deficient LDL uptake (fig. 2)

Case#: Family 1-III:2

CaseHPOs: HP:0003563, HP:0001397 (decreased LDL cholesterol, hepatic steatosis)

CaseNotHPOs: HP:0002910, HP:0000819 (elevated liver enzymes, diabetes)

CasePreviousTesting: TC 104 mg/dl, LDL-C 7 mg/dl, HDL-C 91 mg/dl, TG 31 mg/dl (see additional values in Table 1). Normal ranges- total cholesterol (TC) 92-234 mg/dl, LDL-cholesterol (LDL-C) 136-174 mg/dl, HDL-cholesterol (HDL-C) 60-95 mg/dl), triglyceride (TG) 35-132 mg/dl.

Variant: NM_000384.2:c.2533C>T (p.Gln845Ter), heterozygous

ClinVar: N/A

CAID: CA346011071

gnomAD: 0.000008796 (European non-Finnish)

Case#: Family IV-I:1, male, 84 year old man

CaseHPOs: HP:0003563, HP:0001397 (decreased LDL cholesterol, liver steatosis)

CaseNotHPOs: HP:0000819 (Diabetes)

CasePreviousTesting: TC 106 mg/dl, LDL-C 33 mg/dl, HDL-C 60 mg/dl, TG 60 mg/dl (see additional values in Table 1). Normal ranges- total cholesterol (TC) 92-234 mg/dl, LDL-cholesterol (LDL-C) 136-174 mg/dl, HDL-cholesterol (HDL-C) 60-95 mg/dl), triglyceride (TG) 35-132 mg/dl.

CaseGenotypingMethod: Next generation sequencing panel for high-throughput sequencing of the coding regions of genes previously linked to FHBL (APOB, PCSK9, ANGPTL3) and ABL (MTTP, SAR1B). Sanger sequencing was performed for validation and co-segregation analysis among family members.

Variant: NM_000384.2:c.11153C>G (p.Ser3718Ter), heterozygous

CAID: CA345983128

gnomAD: Absent

Variant evidence: APOB- p.Ser3718* mutations lead to the formation of expected truncated ApoB forms (ApoB-81) of 418 kDa (Fig. 1C, right panel) that can be secreted by the liver and lipidated.

Case#: Family 1-III:1, male, 17 years, son of Family 1-III:2

CaseHPOs: HP:0003563 (decreased LDL cholesterol)

CaseNotHPOs: HP:0000819 (Diabetes mellitus)

CasePreviousTesting: TC 98 mg/dl, LDL-C 14 mg/dl, HDL-C 79 mg/dl, TG 2 mg/dl (see additional values in Table 1). Normal ranges- total cholesterol (TC) 92-234 mg/dl, LDL-cholesterol (LDL-C) 136-174 mg/dl, HDL-cholesterol (HDL-C) 60-95 mg/dl), triglyceride (TG) 35-132 mg/dl.

Variant: NM_000384.2:c.2533C>T (p.Gln845Ter), heterozygous

ClinVar: N/A

CAID: CA346011071

gnomAD: 0.000008796 (European non-Finnish)

Family#: Family IV

PresentingHPOs: HP:0003563 (decreased LDL cholesterol)

PresentingHPOsFreeText: FHBL diagnosis was based on low levels of fasting calculated plasma LDL-C < 50 mg/dL without lipid lowering therapy. Affected relatives were diagnosed by LDL-C < 80 mg/dL and/or ApoB <50 mg/dL.

FamilyMethod1: Next generation sequencing

FamilyGenotypingMethod: Next generation sequencing panel for high-throughput sequencing of the coding regions of genes previously linked to FHBL (APOB, PCSK9, ANGPTL3) and ABL (MTTP, SAR1B). Sanger sequencing was performed for validation and co-segregation analysis among family members.

ProbandLabel: Family IV-I:1

Variant: NM_000384.2:c.11153C>G (p.Ser3718Ter)

CAID: CA345983128

gnomAD: Absent

Case#: Family 1- II:2, female, 49 years

CaseHPOs: HP:0003563 (decreased LDL cholesterol)

CaseNotHPOs: HP:0001397, HP:0000819 (liver steatosis, diabetes)

CasePreviousTesting: TC 143 mg/dl, LDL-C 20 mg/dl, HDL-C 120 mg/dl, TG 18 mg/dl (see additional values in Table 1). ApoB100 <10 mg/dl (normal range 49-88) (Supplemental data) Normal ranges- total cholesterol (TC) 92-234 mg/dl, LDL-cholesterol (LDL-C) 136-174 mg/dl, HDL-cholesterol (HDL-C) 60-95 mg/dl), triglyceride (TG) 35-132 mg/dl.

Variant: NM_000384.2:c.2533C>T (p.Gln845Ter), heterozygous

ClinVar: N/A

CAID: CA346011071

gnomAD: 0.000008796 (European non-Finnish)

Family#: Family 1

PresentingHPOs: HP:0003563 (decreased LDL cholesterol)

PresentingHPOsFreeText: FHBL diagnosis was based on low levels of fasting calculated plasma LDL-C < 50 mg/dL without lipid lowering therapy. Affected relatives were diagnosed by LDL-C < 80 mg/dL and/or ApoB <50 mg/dL.

Family#Method1: Next generation sequencing

Family#GenotypingMethod: Next generation sequencing panel for high-throughput sequencing of the coding regions of genes previously linked to FHBL (APOB, PCSK9, ANGPTL3) and ABL (MTTP, SAR1B). Sanger sequencing was performed for validation and co-segregation analysis among family members.

ProbandLabel: Family 1- II:2

Variant: NM_000384.2:c.2533C>T (p.Gln845Ter)

ClinVar: N/A

CAID: CA346011071

gnomAD: 0.000008796 (European non-Finnish)

FamilyAddInfo: Pedigree Fig 1. The two family members who did not carry the variant presented normal LDL-C levels.

Case: Family III-I:2

CaseHPOs: HP:0003563, (decreased LDL cholesterol)

CaseNotHPOs: HP:0000819 (Diabetes)

CasePreviousTesting: Heterozygous (Chr2:21,230,941; c.8799 G > T; APOBp.Cys2933*) TC 145 mg/dl, LDL-C 55 mg/dl, HDL-C 81 mg/dl, TG 45 mg/dl (see additional values in Table 1). Normal ranges- total cholesterol (TC) 92-234 mg/dl, LDL-cholesterol (LDL-C) 136-174 mg/dl, HDL-cholesterol (HDL-C) 60-95 mg/dl), triglyceride (TG) 35-132 mg/dl.

CaseGenotypingMethod: Next generation sequencing panel for high-throughput sequencing of the coding regions of genes previously linked to FHBL (APOB, PCSK9, ANGPTL3) and ABL (MTTP, SAR1B). Sanger sequencing was performed for validation and co-segregation analysis among family members.

Variant: NM_000384.2:c.8799C>A (p.Cys2933*), heterozygous

CAID: CA345993342

AddInfo: Mother of Family III-II:2. Other daughter (II-1) also has low LDL-C, but no genetic testing results available.

Case: Family IV-III:2, 19 year old female

CaseHPOs: HP:0003563 (decreased LDL cholesterol)

CaseNotHPOs: HP:0000819, HP:0001397 (Diabetes, liver steatosis)

CasePreviousTesting: TC 124 mg/dl, LDL-C 49 mg/dl, HDL-C 62 mg/dl, TG 65 mg/dl (see additional values in Table 1)

Variant: NM_000384.2:c.11153C>G (p.Ser3718Ter), heterozygous

CAID: CA345983128

gnomAD: Absent

Variant evidence: APOB- p.Ser3718* mutations lead to the formation of expected truncated ApoB forms (ApoB-81) of 418 kDa (Fig. 1C, right panel) that can be secreted by the liver and lipidated.

CaseAddInfo: Daughter of Family IV-II:1

Case#: Family IV-III:1, 26 year old, male

CaseHPOs: HP:0003563 (decreased LDL cholesterol)

CaseNotHPOs: HP:0000819 (Diabetes)

CasePreviousTesting: TC 102 mg/dl, LDL-C 36 mg/dl, HDL-C 57 mg/dl, TG 46 mg/dl (see additional values in Table 1)

Variant: NM_000384.2:c.11153C>G (p.Ser3718Ter), heterozygous

CAID: CA345983128

gnomAD: Absent

Variant evidence: APOB- p.Ser3718* mutations lead to the formation of expected truncated ApoB forms (ApoB-81) of 418 kDa (Fig. 1C, right panel) that can be secreted by the liver and lipidated.

CaseAddInfo: Son of Family IV-II:1

Case: Family III-II:2, female, 24 years

CaseHPOs: HP:0003563, (decreased LDL cholesterol)

CaseNotHPOs: HP:0000819 (Diabetes)

CasePreviousTesting: TC 143 mg/dl, LDL-C 28 mg/dl, HDL-C 110 mg/dl, TG 26 mg/dl (see additional values in Table 1). ApoB100 40 mg/dl (normal range 49-88) (Supplemental data). Normal ranges- total cholesterol (TC) 92-234 mg/dl, LDL-cholesterol (LDL-C) 136-174 mg/dl, HDL-cholesterol (HDL-C) 60-95 mg/dl), triglyceride (TG) 35-132 mg/dl.

Variant: NM_000384.2:c.8799C>A (p.Cys2933*), heterozygous

CAID: CA345993342

gnomAD: Absent

Variant evidence: APOB-p.Cys2933* leads to the formation of expected truncated ApoB form (ApoB-64) of 330 kDa (Fig. 1C, right panel) that can be secreted by the liver and lipidated.

Case#: Family IV-II:1, 58 years old, male

CaseHPOs: HP:0003563 (decreased LDL cholesterol)

CaseHPOsFreeText: Type 2 diabetes and severe non-alcoholic steatohepatitis (NASH) with pre-cirrhotic lesions and well differentiated hepatocellular carcinoma (HCC) diagnosed on liver biopsy

CasePreviousTesting: TC 120 mg/dl, LDL-C 50 mg/dl, HDL-C 55 mg/dl, TG 89 mg/dl (see additional values in Table 1) ApoB100 19 mg/dl (normal range 49-88) (Supplemental data)

Variant: NM_000384.2:c.11153C>G (p.Ser3718Ter), heterozygous

CAID: CA345983128

gnomAD: Absent

Variant evidence: APOB- p.Ser3718* mutations lead to the formation of expected truncated ApoB forms (ApoB-81) of 418 kDa (Fig. 1C, right panel) that can be secreted by the liver and lipidated.

CaseAddInfo: Son of Family IV-I:1

Case#: Family II-II:1, 41 year old, male

CaseHPOs: HP:0003563, HP:0001397 (decreased LDL cholesterol, hepatic steatosis)

CaseHPOsFreeText: Prediabetes

CasePreviousTesting: TC 113 mg/dl, LDL-C 38 mg/dl, HDL-C 69 mg/dl, TG 32 mg/dl (see additional values in Table 1). ApoB100 22 mg/dl (normal range 49-88) (Supplemental data). Normal ranges- total cholesterol (TC) 92-234 mg/dl, LDL-cholesterol (LDL-C) 136-174 mg/dl, HDL-cholesterol (HDL-C) 60-95 mg/dl), triglyceride (TG) 35-132 mg/dl.

CaseGenotypingMethod: Next generation sequencing panel for high-throughput sequencing of the coding regions of genes previously linked to FHBL (APOB, PCSK9, ANGPTL3) and ABL (MTTP, SAR1B). Sanger sequencing was performed for validation.

Variant: NM_000384.2:c.7711C>T (p.Gln2571Ter), heterozygous

CAID: CA43502110

gnomAD: Absent

Family#: Family III

PresentingHPOs: HP:0003563 (decreased LDL cholesterol)

PresentingHPOsFreeText: FHBL diagnosis was based on low levels of fasting calculated plasma LDL-C < 50 mg/dL without lipid lowering therapy. Affected relatives were diagnosed by LDL-C < 80 mg/dL and/or ApoB <50 mg/dL.

FamilyMethod1: Next generation sequencing

FamilyGenotypingMethod: Next generation sequencing panel for high-throughput sequencing of the coding regions of genes previously linked to FHBL (APOB, PCSK9, ANGPTL3) and ABL (MTTP, SAR1B). Sanger sequencing was performed for validation and co-segregation analysis among family members.

ProbandLabel: Family III-II:2

Variant: NM_000384.2:c.8799C>A (p.Cys2933*), heterozygous

CAID: CA345993342

gnomAD: Absent

Family#: Family M

PresentingHPOs: HP:0003563 (decreased LDL cholesterol concentration)

PresentingHPOsFreeText: <5th percentile for LDL cholesterol

CountryOrigin: United States

Ethnicity: Caucasian

Race:

Family#PreviousTesting: No other genetic testing performed.

Family#Method1: PCR

Family#Method2: Sanger sequencing

Family#GenotypingMethod: PCR amplification of the entire APOB coding region, exon/intron junctions, 5' upstream, 5' and 3' untranslated regions, followed by cloning and sequencing in proband. Slot blot analysis of genomic DNA from family members.

AddSegregationInfo: Father (43 yo) and two sibs of the proband are heterozygous for an APOB variant and have <5th percentile LDL-cholesterol (47 mg/dl, 29 md/dl, and 16 mg/dl respectively)) based on https://www.ncbi.nlm.nih.gov/books/NBK351/ (Table 31.9); LDL-cholesterol level was no available for the mother but she is heterozygous for an APOB variant; two affected sibs have 0 LDL-cholesterol and are compound heterozygous.

ProbandLabel: CM (II:3)

Variant: Compound heterozygous: Variant 1: NM_000384.2:c.537+1G>T (paternal) Variant 2: NM_000384.2:c.1315C>T (p.Arg439Ter) (maternal)

ClinVar: N/A

CAID: Variant 1: CA345962364 ; Variant 2: CA052017

gnomAD: Variant 1: Not in gnomAD; Variant 2: 0.00002640 (Euro non-Finnish)

FamilyAddInfo: Inheritance pattern is consistent with semi-dominant, in that father and both heterozygous sibs have low levels of LDL-cholesterol (levels not available for mother), which rules out abetalipoproteinemia (in which heterozygotes have normal LDL-cholesterol levels).

Case#: CM (II:3), deceased at age 18 years.

CaseHPOs: HP:0002024, HP:0002013, HP:0002570, HP:0001251, HP:0001260, HP:0002495, HP:0001284 (malabsorption, vomiting, steatorrhea, ataxia, dysarthria, impaired vibratory sensation, absent deep tendon reflexes)

CaseHPOsFreeText: Symptoms as early as 4 months of age. Diagnosed with FHBL at 10 month; treatment with medium chain triglycerides (MCT) led to weight gain and a decrease in steatorrhea. Abnormalities in liver function, micronodular cirrhosis at 30 months, thought to be caused by treatment with MCT, progression to portal hypertension and esophageal varices. Neurologic symptoms stabilized on vitamin E therapy. At age 15, hepatitis A and cholelithiasis. He developed seizures, had a cerebrovascular accident, recurrent massive gastrointestinal hemorrhages, and finally cardiac arrest at the age of 18 (further details in PMID: 4135110).

CasePreviousTesting: No detectable plasma apoB by radial immunodiffusion (PMID: 4135110), Total cholesterol 36 mg/dl, triglyceride 12 mg/dl, no detectable LDL-cholesterol, HDL-cholesterol 36 mg/dl at age 15 years. No genetic testing other than APOB sequencing.

CaseGenotypingMethod: See family method

Variant: Compound heterozygous:

Variant 1: NM_000384.2:c.537+1G>T (paternal)

Variant 2: NM_000384.2:c.1315C>T (p.Arg439Ter) (maternal)

ClinVar: N/A

CAID: Variant 1: CA345962364 ; Variant 2: CA052017

gnomAD: Variant 1: Not in gnomAD;<br /> Variant 2: 0.00002640 (Euro non-Finnish)

CasePMIDs: 4135110

Case#: (Biallelic affected sib) MM, female, 10 years (at age of blood draw) CaseHPOs: HP:0002024, HP:0002013, HP:0002570, HP:0002495, HP:0001284 (malabsorption, vomiting, steatorrhea, , impaired vibratory sensation, absent deep tendon reflexes)

CaseHPOsFreeText:: Diagnosed with FHBL at age 10 years; neurological symptoms stabilized on Vitamin E treatment. CasePreviousTesting: Total cholesterol 24mg/dl, no detectable triglyceride ot LDL-cholesterol, 21 mg/dl HDL cholesterol. Variant: Compound heterozygous: Variant 1: NM_000384.2:c.537+1G>T (paternal) Variant 2: NM_000384.2:c.1315C>T (p.Arg439Ter) (maternal)

ClinVar: N/A

CAID: Variant 1: CA345962364 ; Variant 2: CA052017

gnomAD: Variant 1: Not in gnomAD; Variant 2: 0.00002640 (Euro non-Finnish)

Case#: (Heterozygous sib) GM (II-5), male, 14 years (at blood draw), sib of proband CaseHPOs: HP:0003563 CaseHPOsFreeText: Asymptomatic CasePreviousTesting: Total cholesterol 97 mg/dl, triglyceride 59 mg/dl, LDL-cholesterol 29 mg/dl (<5th percentile), HDL cholesterol 56 mg/dl. ** Variant:** Heterozygous for NM_000384.2:c.537+1G>T (paternal)

CAID: CA345962364

Case#: (Heterozygous sib) JM (II-6), male, 7 years (at blood draw), sib of proband CaseHPOs: HP:0003563 CaseHPOsFreeText: Asymptomatic CasePreviousTesting: Total cholesterol 113 mg/dl, triglyceride 60 mg/dl, LDL-cholesterol 16 mg/dl (<5th percentile), HDL cholesterol 87 mg/dl) ** Variant:** Heterozygous for NM_000384.2:c.1315C>T (p.Arg439Ter) (maternal)

CAID: CA052017

Case# Patient 5, Caucasian, Female, age 61

CasePreviousTesting Screened for prevalent European mutations in apoB with DGGE.

CasePresenting HPOs HP:0005145 Narrowing of Coronary Artery and HP:0003124 Hypercholesterolemia

CaseNotHPOs n/a

CaseGenotypingMethod PCR fraction of exom 26, denaturing gradiant gel electrophoresis

Variant NM_000384.2(APOB):c.10580G>A (p.Arg3527Gln)

ClinVar 17890

gnomAD 0.0005791 gnomaD

VariantEvidence high LDL-cholesterol levels(mg/dl) P5=240, PMID: 3477815- reduced LDLR affinity

CaseAddInfo significantly lower fractional catabolic rate/production rate according to pending model

Case# Patient 1, Caucasian, Male, 69-- Patient 2, Caucasian, Male, 64-- Patient 3, Caucasian, Male, 49-- Patient 4, Caucasian, Male, 42

CasePreviousTesting Screened for prevalent European mutations in apoB with DGGE.

CasePresenting HPOs HP:0005145 Narrowing of Coronary Artery and HP:0003124 Hypercholesterolemia

CaseNotHPOs n/a

CaseGenotypingMethod PCR fraction of exom 26, denaturing gradiant gel electrophoresis

Variant NM_000384.2(APOB):c.10708C>T (p.His3570Tyr)

ClinVar 431988

gnomAD 0.0002614 gnomaD

VariantEvidence high LDL-cholesterol levels(mg/dl) P1=18, P2=62, P3=174, P4=154,

CaseAddInfo significantly lower fractional catabolic rate/production rate according to pending model

NonHumanModel Mus musculus

GeneAlteration Transgenic mouse-modified gene (C57BL/6XSJL) inserted into fertilized mouse eggs

ModelPhenotype HP:0003124 Hypercholesterolemia

HumanPhenotype HP:0003124 Hypercholesterolemia

ModelEvidence Demonstrated low binding affinity of mouse and patient LDL compared to healthy control (fig. 4). Also, tested to make sure other common ligands of the receptor did not compete with the mutant apoB and sway the data (fig. 5 B,C,D). Tested to be sure that differential binding was not influenced by expression levels of apoB in R3500Q mutant using 2 other mutants (R3500G, R3500K) with different expression levels (fig. 5 A.

ModelVariant NM_000384.2(APOB):c.10580G>A (p.Arg3527Gln), ClinVar ID: 17890

Family#: RW kindred

PresentingHPOs: Heterozygotes (n = 14) had 44% normal level total cholesterol, 67% normal level LDL cholesterol, and 67% normal level apoB-100 concentrations compared with unaffected family members (n = 20), and significant mean increases in the liver enzymes alanine aminotransferase (3.8 times), aspartate aminotransferase (1.6 times), and γ-glutamyltransferase (3.0 times), and intermediate levels of serum α–tocopherol. No family member had the apoε2 isoform, ruling out this variant as a possible contributor to hypolipoproteinemia.

CountryOrigin: Lebanon (Christian)

Family#Method1: PCR

Family#Method2: Sanger sequencing

Family#GenotypingMethod: “DNA sequence analysis of the entire human APOB gene”

Affected: 2 homozygotes, 14 heterozygotes

Unaffected: 20 (i.e. homozygous normal)

PublishedLOD: 9.63 at 0% recombination fraction (for biochemical, semi-dominant phenotype)

ProbandLabel: Subject III:6

Variant: NM_000384.2:c.1468C>T (p. Arg490Trp)

ClinVar: N/A

CAID: CA053659

gnomAD: 0.00001759 (European non-Finnish)

FamilyPMIDs: PMID 8412898 (previous publication with analysis of fewer family members)