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

CA014494

42992 (ClinVar)

Gene: MYH7

Condition: hypertrophic cardiomyopathy

Inheritance Mode: Autosomal dominant inheritance

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

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

• Met criteria codes: PP1_Strong PS4 PP3 PM2

• Not Met criteria codes: PS3 PS1 PS2 PM5 PM4 PM3 PM6 PM1 BA1 BS4 BS3 BS1 BS2 BP7 BP2 BP4 BP3

Expert Panel

Cardiomyopathy VCEP

Criteria Specification Information

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.

Met criteria codes

• 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%)

Not Met criteria codes

• 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
• 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
• BA1: Allele frequency of 0.0004% in gnomAD
• 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
• BS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• 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.

Approved on: 2021-11-23

Published on: 2021-12-09