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]

Variant: NM_000257.4(MYH7):c.1012G>A (p.Val338Met)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA010061

164381 (ClinVar)

Gene: MYH7

Condition: hypertrophic cardiomyopathy

Link to MONDO

UUID: 0fb73aff-c7e0-4250-bc83-dd47e679755e

Approved on: 2021-09-27

Published on: 2021-10-01

HGVS expressions

NM_000257.4:c.1012G>A

NM_000257.4(MYH7):c.1012G>A (p.Val338Met)

NC_000014.9:g.23429901C>T

CM000676.2:g.23429901C>T

NC_000014.8:g.23899110C>T

CM000676.1:g.23899110C>T

NC_000014.7:g.22968950C>T

NG_007884.1:g.10761G>A

ENST00000355349.4:c.1012G>A

ENST00000355349.3:c.1012G>A

NM_000257.3:c.1012G>A

Likely Pathogenic

PM1 PM2 PP1_Moderate PS4_Moderate

PP3 PM6 PM4 PM5 PVS1 BA1 BS4 BS3 BS1 BP3 BP5 BP2 BP7 BP4 PS3 PS2 PS1

Evidence Links 0

Expert Panel

Cardiomyopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Cardiomyopathy VCEP

The NM_000257.4(MYH7):c.1012G>A (p.Val338Met) variant in MYH7 has been identified in at least 11 individuals with HCM (PS4_Moderate; Homburger 2016 PMID:27247418; Walsh 2017 PMID:27532257; Ambry, pers. comm.; Centenary Institute Sydney pers. comm.; GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.), and at least in a presumably unaffected individual (<40 years old) with a family history of HCM (Valente 2013 PMID: 23690394; Captur 2014 PMID:25228707). This variant segregated with disease in 6 affected relatives with HCM from 3 families (PP1_Moderate, GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.). This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.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 associated with HCM (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate, PP1_Moderate; PM2, PM1.

PM1

Located in myosin head domain.

PM2

Absent from population databases. Good coverage at this position in gnomAD.

PP1_Moderate

Six meioses

PS4_Moderate

Identified in 11 probands with HCM.

PP3

REVEL score = 0.734, which is greater than the 0.7 cutoff used in our laboratory. Not conserved in lower mammals, not met to be more conservative

PM6

No de novo occurrences reported.

PM4

Not an inframe indel

PM5

Other variants reported in this codon appear to be VUSes.

PVS1

Not a null variant

BA1

Absent from population databases

BS4

No non-segregation in affected individuals reported

BS3

Functional studies not performed.

BS1

Absent from population databases

BP3

Not an inframe indel

BP5

None of the reported probands had additional path/likely path variants.

BP2

Not reported in trans with a pathogenic variant.

BP7

Not a silent/intronic variant

BP4

REVEL score = 0.734

PS3

Functional studies not performed.

PS2

No de novo occurrences reported.

PS1

None found

Curation History

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