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.4130C>T (p.Thr1377Met)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA014494

42992 (ClinVar)

Gene: MYH7

Condition: hypertrophic cardiomyopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: f4dea66d-87b3-467f-862c-c239472e6930

Approved on: 2021-11-23

Published on: 2021-12-09

HGVS expressions

NM_000257.4:c.4130C>T

NM_000257.4(MYH7):c.4130C>T (p.Thr1377Met)

NC_000014.9:g.23418249G>A

CM000676.2:g.23418249G>A

NC_000014.8:g.23887458G>A

CM000676.1:g.23887458G>A

NC_000014.7:g.22957298G>A

NG_007884.1:g.22413C>T

ENST00000355349.4:c.4130C>T

ENST00000355349.3:c.4130C>T

NM_000257.3:c.4130C>T

Pathogenic

PP1_Strong PS4 PP3 PM2

BS2 BS4 BS3 BS1 BP7 BP2 BP4 BP3 PS3 PS1 PS2 BA1 PM5 PM4 PM3 PM6 PM1

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.4130C>T (p.Thr1377Met) variant in MYH7 has been reported in >30 individuals with HCM (PS4; Richard 2003 PMID: 12707239; Van Driest 2004 PMID: 15358028; Girolami 2006 PMID: 16858239; Millat 2010 PMID: 20624503; Witjas-Paalberends 2013 PMID: 23674513; Berge 2014 PMID: 24111713; Helms 2014 PMID: 25031304; Adler 2016 PMID: 26743238; Montag 2017 PMID: 29101517; Pérez-Sánchez 2018 PMID: 28687478; Wang 2018 PMID: 29343710; Ambry pers. comm.; CHEO pers. comm.; GeneDx pers. comm., Invitae pers. comm.; LMM pers. comm.; Mayo pers. comm.; OMGL pers. comm.). This variant segregated with disease in >10 affected relatives with HCM in at least 4 families (PP1_strong; Pérez-Sánchez 2018 PMID: 28687478; Wang 2018 PMID: 29343710; LMM pers. comm.). This variant was identified in 0.0009% (1/113754) of European chromosomes by gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). 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; PP1_Strong; PM2; PP3.

PP1_Strong

>15 segs from 7 families

PS4

>15 probands reported in the literature and by laboratories in the Internal Data Log

PP3

In silico analysis programs (SIFT, PolyPhen-2, Mutation Taster) predict this variant to have an impact on the protein function.

PM2

Allele frequency of 0.0004% in gnomAD (global) Seen in 1/113754 european alleles in gnomad (0.0009%)

BS2

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

BS4

No evidence of non-segregation available in the literature or the Internal Data Log

BS3

Functional Data not available for this variant at this time.

BS1

Allele frequency of 0.0004% in gnomAD

BP7

This is a missense variant.

BP2

n/a

BP4

In silico analysis programs (SIFT, PolyPhen-2, Mutation Taster) predict this variant to have an impact on the protein function.

BP3

This is a missense variant.

PS3

Functional Data not available for this variant at this time.

PS1

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

PS2

no reports of denovo

BA1

Allele frequency of 0.0004% in gnomAD

PM5

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

PM4

This is a missense variant.

PM3

n/a

PM6

no reports of denovo

PM1

not in hotspot

Curation History

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