Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

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Variant: NM_000257.3(MYH7):c.2221G>T (p.Gly741Trp)

CA012022

177665 (ClinVar)

Gene: MYH7

Condition: hypertrophic cardiomyopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 6c7676cc-a729-42ee-bc9c-580feb015c57

HGVS expressions

NM_000257.3:c.2221G>T

NM_000257.3(MYH7):c.2221G>T (p.Gly741Trp)

NM_000257.4:c.2221G>T

ENST00000355349.3:c.2221G>T

NC_000014.9:g.23425760C>A

CM000676.2:g.23425760C>A

NC_000014.8:g.23894969C>A

CM000676.1:g.23894969C>A

NC_000014.7:g.22964809C>A

NG_007884.1:g.14902G>T

Pathogenic

PP1_Moderate PS4 PP3 PM2 PM5 PM1

Evidence Links 3

Expert Panel

Cardiomyopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Cardiomyopathy VCEP

The c.2221G>T (p.Gly741Trp) variant in MYH7 has been reported in >15 individuals with hypertrophic cardiomyopathy (PS4; PMID: 8533830; PMID:15856146; PMID:27532257; Partners LMM ClinVar SCV000203910.4; AGCMC Sydney ClinVar SCV000212638.1). This variant segregated with disease in 5 affected individuals (PP1_Moderate; PMID:15856146; AGCMC Sydney ClinVar SCV000212638.1). This variant was absent from large population studies (PM2; http://exac.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). A different pathogenic missense variant has been previously identified at this codon which may indicate that this residue is critical to the function of the protein (PM5; c.2221G>C p.Gly741Arg - Variation ID 14098). In summary, this variant meets criteria to be classified as pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4; PM1; PM2; PM5; PP1_Moderate; PP3

PP1_Moderate

5 segregations including SCV000212638.1

Variant segregated with disease PubMed:15856146

Variant segregated with disease in 3 affected family members PubMed:8533830

PS4

>15 probands including ClinVar SCV000203910.4 and ClinVar SCV000212638.1

Variant found in probands with HCM PubMed:27532257

PP3

Tools predict damaging

PM2

Absent from ExAC

PM5

c.2221G>C (p.Gly741Arg) - Variation ID 14098 - Pathogenic by Expert Panel

PM1

Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated

Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated PubMed:27532257

Approved on: 2016-12-15

Published on: 2018-11-16

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