Lots of variants!!!

PMID:33067490

Gene: BRCA2

PMID: 28790153

Gene: MYH7

HGNC:7577

CaseAJV: 17 years diagnosis, Australia

DiseaseAssertion: Hypertrophic Cardiomyopathy

FamilyInfo: Father (index case) died awaiting cardiac transplant (carried both variants). Two possibly affected relatives.

CasePresentingHPOs: HP:0001639, HP:0006536

(Hypertrophic cardiomyopathy, Obstructive lung disease)

HPOsFreeText: Maximum left ventricular hypertrophy at 17 mm, Sudden cardiac death event at 17 years, Maximal wall thickness at 22mm,

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CasePreviousTesting: See Table 1

CaseGenotypingMethod: DNA was isolated from peripheral blood. Most participants underwent testing from the Illumina Cardiomyopathy Sequencing Panel, which includes 46 cardiomyopathy related genes. For others, whole exome sequencing or Sanger squencing was used. After the results were returned, variants were filtered for pathogenicity and rarity.

Variant:NM_000257.3:c.1954A>G (p.Arg652Gly)

ClinVarID:177626 https://www.ncbi.nlm.nih.gov/clinvar/variation/177626/

gnomAD: Not in gnomAD

Multiple Gene Variants:

MYBPC3 Variant

Variant: NM_000256.3:c.2980C>T (p.Leu994Phe)

ClinVarID:180992 https://www.ncbi.nlm.nih.gov/clinvar/variation/180992/

gnomAD: European (Non-Finnish) 1.624e-4, Overall 8.461e-5 https://gnomad.broadinstitute.org/variant/11-47355487-G-A

Monarch lookup result: https://monarchinitiative.org/phenotype/HP:0000252

Monarch lookup result: https://monarchinitiative.org/phenotype/HP:0000750

Monarch lookup result: https://monarchinitiative.org/phenotype/HP:0001249

Monarch lookup result: https://monarchinitiative.org/phenotype/HP:0001249

variant id lookup result: https://www.ncbi.nlm.nih.gov/clinvar/variation/559601/

Monarch lookup result: https://monarchinitiative.org/phenotype/HP:0001263

allele id lookup result: https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA346813374

allele id lookup result: https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA346764646

Monarch lookup result: https://monarchinitiative.org/phenotype/HP:0000252

allele id lookup result

Monarch lookup result: https://monarchinitiative.org/phenotype/HP:0001250

Monarch lookup result: https://monarchinitiative.org/phenotype/HP:0031936

variant id lookup result

Monarch lookup result: https://monarchinitiative.org/phenotype/HP:0002019

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Monarch lookup result: https://monarchinitiative.org/phenotype/HP%3A0000002

Monarch lookup result: https://monarchinitiative.org/phenotype/HP%3A0000271

Monarch lookup result: https://monarchinitiative.org/phenotype/HP:0002360

Monarch lookup result: https://monarchinitiative.org/phenotype/HP:0000708

Monarch lookup result: https://monarchinitiative.org/phenotype/HP:0001263

This figure has been updated to reflect the current curation workflow and approval process.

New section that outlines examples on how to score Semidominant mode of inheritance in the GCI.

Using these PMIDs allows a curator to score applicable evidence within the GCI that is included as part of a general, large resource database.

This section was updated to include new useful websites, including PMIDs to use for curation purposes on websites that may house important evidence (e.g. The Human Protein Atlas, MGI, IMPC, etc). A new section entitled Case-Level databases was added to provide curators with information on well-known sites containing case-level genetic evidence that may be applicable to scoring for a given gene-disease relationship.

This section was updated to reflect new references

New section that outlines the procedures for all GCEPs to follow for recuration of gene-disease relationships under their purview. A hyperlink to the full recuration document is included.

New section that outlines additional information to consider for the final classification summary.

This section has been updated to reflect the current curation workflow using the GCI.

Updated section that provides guidance and recommendations for upgrading and downgrading default variant scores based on several lines of evidence, including mode of inheritance, computational predictors, population frequency, disease mechanism, phenotype, and constraint metrics.

New section that provides guidance and recommendations for scoring founder variants in a given gene-disease relationship.

New section that provides examples, guidance and recommendations for the evaluation of recurrent variants, or variants that have been observed multiple times for a given gene-disease relationship.

New section that outlines important information on the matrix including max points per variant type and category, and information on how to manually override a calculated gene-disease validity classification in the GCI (visual representation on Figure 4, p18).

New section that outlines the purpose of the default and range scores per case.

This section has been updated to include additional useful publication search engines.

New section that outlines the current “Mode of inheritance” (MOI) options available in the GCI and how they affect the ability to score and/or publish gene-disease validity classifications to the website. A new table visually outlines the MOIs and scoring, approving, and publishing capabilities (Table 1).

This is a new section outlining the process of selecting a gene, disease, and mode of inheritance. Hyperlinks to supportive resources, such as the ClinGen Lumping and Splitting guidelines, GeneTracker, etc. are provided.

The classification of “No reported Evidence” has been updated to “No known disease relationship” in order to align with the new terminology recommendation from the international Gene Curation Consortium (GenCC).

This section has been updated to reflect our current curation workflow.

Information on Hypothes.is and a hyperlink to the Hypothes.is Annotation SOP is now included. This web-based annotation tool is used by many GCEPs, and has been shown to significantly reduce curation time.

The Hypothes.is Gene Annotations SOP version 1 is located under the "Additional Supporting Materials Tab."

This protocol outlines procedures for annotating and tagging applicable gene curation evidence and is structured to capture fields required for the ClinGen Gene curation Interface (GCI).

To see Hypothes.is annotated notes on the SOP, click the hyperlink on the webpage titled "Gene-Disease Validity Standard Operating Procedures, Version 7"

The Hypothes.is Gene Annotations SOP version 1 is located under the "Additional Supporting Materials Tab."

This protocol outlines procedures for annotating and tagging applicable gene curation evidence and is structured to capture fields required for the ClinGen Gene curation Interface (GCI).

To see Hypothes.is annotated notes on the SOP, click the hyperlink on the webpage titled "Gene-Disease Validity Standard Operating Procedures, Version 7"

ClinGen Gene-Disease Validity Standard operating Procedures Version 7 was released on August 12, 2019.

The Table of Contents is now interactive and “clickable.” Clicking on a section title will take the reader to the section of interest.

Click the following link to see SOP version 7 updates using Hypothes.is annotation. These notes will be similar to the HIGHLIGHTED version of the SOPv7.

Monarch lookup result: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6276694/

Monarch lookup result: https://monarchinitiative.org/disease/MONDO:0005635

ClinVar variant ID lookup result https://www.ncbi.nlm.nih.gov/clinvar/variation/156152/

Monarch lookup result: https://monarchinitiative.org/phenotype/HP:0000121

Monarch lookup result: https://monarchinitiative.org/phenotype/HP:0001947

Monarch lookup result: https://monarchinitiative.org/phenotype/HP:0004912

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Monarch lookup result: https://monarchinitiative.org/disease/MONDO:0009297

Monarch lookup result: https://monarchinitiative.org/phenotype/HP:0000124

Monarch lookup result: https://monarchinitiative.org/phenotype/HP:0001943

Monarch lookup result: https://monarchinitiative.org/phenotype/HP:0005949

ClinVar variant ID lookup result https://www.ncbi.nlm.nih.gov/clinvar/variation/156152/

Monarch lookup result: https://monarchinitiative.org/phenotype/HP:0002448

ClinVar variant ID lookup result: https://www.ncbi.nlm.nih.gov/clinvar/variation/427942/

ClinVar variant ID lookup result: https://www.ncbi.nlm.nih.gov/clinvar/variation/427941/

Monarch lookup result: https://monarchinitiative.org/phenotype/HP:0007375

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Mseqdr lookup result: https://mseqdr.org/hpo_browser.php?11968;

Monarch lookup result: https://monarchinitiative.org/phenotype/HP:0003808

Monarch lookup result: https://monarchinitiative.org/phenotype/HP:0008936

ClinVar variant ID lookup result: https://www.ncbi.nlm.nih.gov/clinvar/variation/427942/

ClinVar variant ID lookup result: https://www.ncbi.nlm.nih.gov/clinvar/variation/427941/

Monarch lookup result: https://monarchinitiative.org/phenotype/HP:0008386

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Monarch lookup result: https://monarchinitiative.org/phenotype/HP:0000926

Monarch lookup result: https://monarchinitiative.org/phenotype/HP:0001943

ClinVar variant ID lookup result: https://www.ncbi.nlm.nih.gov/clinvar/variation/417794/

ClinVar variant ID lookup result: https://www.ncbi.nlm.nih.gov/clinvar/variation/417796/

Mseqdr lookup result: https://mseqdr.org/hpo_browser.php?4060;

Monarch lookup result: https://monarchinitiative.org/phenotype/HP:0003375

Monarch lookup result: https://monarchinitiative.org/phenotype/HP:0000926

ClinGen allele ID lookup result: https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_001440.3%3Ac.953C%3ET

Monarch lookup result: https://monarchinitiative.org/phenotype/HP:0005306

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Monarch lookup result: https://www.sciencedirect.com/science/article/pii/S0888754300964784?via%3Dihub