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]

Link to SEPIO compliant JSON-LD document

Variant: NM_000257.3(MYH7):c.2360G>A (p.Arg787His)

CA012239

42900 (ClinVar)

Gene: MYH7

Condition: hypertrophic cardiomyopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: de961e5a-a5f1-47f5-abee-524b09b41cc0

Approved on: 2021-04-27

Published on: 2021-06-16

HGVS expressions

NM_000257.3:c.2360G>A

NM_000257.3(MYH7):c.2360G>A (p.Arg787His)

ENST00000355349.4:c.2360G>A

ENST00000355349.3:c.2360G>A

NM_000257.4:c.2360G>A

NC_000014.9:g.23425345C>T

CM000676.2:g.23425345C>T

NC_000014.8:g.23894554C>T

CM000676.1:g.23894554C>T

NC_000014.7:g.22964394C>T

NG_007884.1:g.15317G>A

Likely Benign

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Conflicting Evidence"

PM1 BS1 BP2

PP3 BA1 PM5 PM2 PS4 BP4

Evidence Links 2

Expert Panel

Cardiomyopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Cardiomyopathy VCEP

The c.2360G>A (p.Arg787His) variant in MYH7 has been identified in 0.10% (FAF 95% CI; 41/30616) of South Asian chromosomes in gnomAD v2.1.1 (https://gnomad.broadinstitute.org), which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BS1; Kelly 2018 PMID:29300372). Allowing a variant to reach a likely benign classification based on BS1 alone represents a revision of the original ACMG/AMP framework by ClinGen’s Sequence Variant Interpretation Working Group (Tavtigian 2018 PMID: 29300386). Additionally, while 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; Walsh 2017 PMID:27532257), this pathogenic evidence code (PM1) was not considered to be in conflict with a likely benign conclusion. In summary, this variant meets criteria to be classified as likely benign for cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): BS1, PM1.

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

BS1

This variant has been identified in 0.1% (FAF 95% CI; 41/30616) of South Asian chromosomes in gnomAD v2.1.1 (https://gnomad.broadinstitute.org), which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BS1; PMID:29300372). (Technically can be BA1, too liberal?)

BP2

Variant identified in multiple affected individuals with other pathogenic variants (including ClinVar SCV000059440.5 and SHaRe data)

Variant identified in 2 probands with HCM - however both carry pathogenic variants in other genes PubMed:21959974

PP3

Comp and cons conflicting, revel score not low enough

BA1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PM5

2 VUS, one multiple submitter, 1 single submitter

PM2

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PS4

PM2 not met

BP4

Comp and cons conflicting, revel score not low enough

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