third case
Case#: Patient 303-002, female, N. European; 16 years old at report in PMID: 1428198 (Case 3)
CaseHPOs: CaseHPOsFreeText: “Peculiar peripheral fundus pigmentation” was noted on eye exam at age 12 years, “slight difficulty in the dark” (PMID 1428198, Case 3). Fundus and ERG abnormalities reported to be characteristic of Oguchi disease. ERG abnormalities included, after 45 min of dark adaptation, a nondetectable rod response to single flashes of dim blue light and a normal cone response to 30-Hz white flickering light.
CaseNotHPOsFreeText: Visual acuity was 20/20 bilaterally at age 16 years. Eye exam was normal except for fundus changes. Normal physical examination, laboratory tests (no details given on which tests were performed), and x-rays (no details given on which bones were X-rayed)(PMID: 1428198)
CasePreviousTesting: No variants identified in SAG (by SSCP analysis). The authors note specifically that SAG Asn309(1-bp del) was absent (a positive control with this variant was included in the study).
CaseMethod1: SSCP
CaseMethod2: Sequencing
CaseGenotypingMethod: Single-strand conformation polymorphism (SSCP) analysis of the coding exons and exon/intron boundaries of GRK1 and SAG.
Variant: 1) NM_002929.3(GRK1):c.1139T>A (p.Val380Asp) (paternal) 2) NM_002929.2:c.1607_1610del (p.Asp537ValfsTer7) (maternal)
ClinVar: 1) 13010; 2) N/A
CAID: 1) CA034664; 2) CA7066374
gnomAD: 1) 0.00006786 (European non-Finnish, 5 alleles total, no homozygotes) 2) 0.001541 (South Asian; 89 alleles total in all populations; no homozygotes)
VariantEvidence: p.Val380Asp introduces a negatively charged residue into the catalytic domain and would therefore likely interfere with kinase activity. However, no functional studies are available.
CaseAddInfo: Family #F277 (Figure 2)- The father is heterozygous for c.1139T>A (p.Val380Asp), and the mother is heterozygous for c.1607_1610del. Her affected sister (Case 4 in PMID: 14281981) has the same genotype as 303-002. Two unaffected brothers are heterozygous for p.Val380Asp. Both sets of grandparents are from the same small town in Hungary (PMID: 14281981).
CasePMIDs: 14281981
Score: 1. This individual and her sister have classic features of Oguchi disease and both are compound heterozygous for a missense variant (p.Val380Asp) and a frameshift variant in GRK1. SAG analysis, by SSCP, was normal. The highest population minor allele frequencies of these variants in gnomad v2.1.1 are 0.00006786 (European non-Finnish, 5 alleles total, no homozygotes) and 0.001541 (South Asian; 89 alleles total in all populations; no homozygotes) respectively. The score is reduced because SAG was analyzed by SSCP and hence it is possible that causative variants in that gene may have been missed, and because there is no functional evidence to support the deleterious impact of the missense change.