Variant: NM_000257.3(MYH7):c.1157A>G (p.Tyr386Cys)

CA010299

164378 (ClinVar)

Gene: MYH7

Condition: cardiomyopathy

Inheritance Mode: Autosomal dominant inheritance

UUID: 821dbd1d-4ca7-4f58-8a42-0ec982d8eb66

HGVS expressions

NM_000257.3:c.1157A>G
NM_000257.3(MYH7):c.1157A>G (p.Tyr386Cys)
NC_000014.9:g.23429329T>C
CM000676.2:g.23429329T>C
NC_000014.8:g.23898538T>C
CM000676.1:g.23898538T>C
NC_000014.7:g.22968378T>C
NG_007884.1:g.11333A>G
ENST00000355349.4:c.1157A>G
ENST00000355349.3:c.1157A>G
NM_000257.4:c.1157A>G
NM_000257.4(MYH7):c.1157A>G (p.Tyr386Cys)

Likely Pathogenic

• Met criteria codes: PP3 PM6 PM1 PM2 PS4_Supporting

• Not Met criteria codes: BP4 PS1 PM5

Expert Panel

Cardiomyopathy VCEP

Criteria Specification Information

Evidence submitted by expert panel

Cardiomyopathy VCEP

The NM_000257.4(MYH7):c.1157A>G (p.Tyr386Cys) variant has been reported as a de novo occurence in 2 infants with early-onset/severe cardiomyopathy that presented with variable features (1 with features of HCM and RCM, and 1 with features of HCM and LVNC that progressed to DCM; Lakdawala 2012 PMID:22464770; Greenway 2012 PMID:23170025; Alfares 2015 PMID:25611685; LMM pers. comm.) and in an additional case with RCM (age unknown; GeneDx pers. comm.). Collectively, this data meets criteria for PS4_Supporting and PM6. 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 analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for complex cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Supporting, PM6, PM2, PM1, PP3.

Met criteria codes

• PP3: Below predictions not working, but all tools available in Franklin predict damaging, as does REVEL with score of 0.91
• PM6: De novo occurrence in 2 infants with cardiomyopathy (LMM data, also reported in Alfares 2015)
• PM1: Variant occurs in the head domain (aa 181-937)
• PM2: Absent from gnomAD v.2.1.1 with good coverage
• PS4_Supporting: The NM_000257.4(MYH7):c.1157A>G (p.Tyr386Cys) variant has been reported as de novo in 2 infants with early-onset/severe cardiomyopathy that presented with variable features (HCM, RCM, DCM, and LVNC; Lakdawala 2012 PMID:22464770; Greenway 2012 PMID:23170025; Alfares 2015 PMID:25611685; LMM pers. comm.) and an additional case of unknown age with RCM (GeneDx pers. comm.). Collectively, this data meets criteria for PS4_Supporting and PM6. Lakdawala (2012) J Card Fail 18: 296 PubMed: 22464770 - Identified in 1 infant with DCM (cohort tested for DCM and then diagnosis verified by clinical information). Original VCEP assessment lists this is the LMM case with "HCM & LVNC" and that it was de novo (w/o paternity confirmed). Greenway (2012) Circ Heart Fail 5: e92 PubMed: 23170025 - Case report of infant with clinical diagnosis of RCM with associated myocardial hypertrophy; testing performed by LMM. Patient deceased at 18 months old and trabeculations observed upon autopsy. Alfares (2015) Genet Med 17: 880 PubMed: 25611685 - Reported in 1 patient with HCM as de novo (parentage not confirmed); LMM paper Walsh (2017) Genet Med 19: 192 PubMed: 27532257 - Reported in 1 case sent for HCM testing by LMM LMM - 1 proband has HCM and RCM, another proband has HCM and possible LVNC. Both are infants and variant is presumed denovo in both cases (Parentage not confirmed) GeneDx - 1 case with RCM

Not Met criteria codes

• BP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM5: Only other change at this position in ClinVar is a synonmous change that is LB. HGMD has c.1156T>C (p.Tyr386His) entry with a single publication. Did not investigate further.

Approved on: 2021-11-30

Published on: 2021-12-09