Variant: NM_000257.4(MYH7):c.5740G>A (p.Glu1914Lys)

CA016441

43088 (ClinVar)

Gene: MYH7

Condition: dilated cardiomyopathy

Inheritance Mode: Autosomal dominant inheritance

UUID: 4d2aa3fa-3052-415e-9f35-66031cc8266c

HGVS expressions

NM_000257.4:c.5740G>A
NM_000257.4(MYH7):c.5740G>A (p.Glu1914Lys)
ENST00000355349.4:c.5740G>A
ENST00000355349.3:c.5740G>A
NM_000257.3:c.5740G>A
NC_000014.9:g.23413809C>T
CM000676.2:g.23413809C>T
NC_000014.8:g.23883018C>T
CM000676.1:g.23883018C>T
NC_000014.7:g.22952858C>T
NG_007884.1:g.26853G>A

Likely Pathogenic

• Met criteria codes: PS4_Moderate PS2 PP3 PM2

• Not Met criteria codes: BS4 BS3 BS1 BP4 PS3 PS1 BA1 PP1 PM1 PM6

Expert Panel

Cardiomyopathy VCEP

Criteria Specification Information

Evidence submitted by expert panel

Cardiomyopathy VCEP

The c.5740G>A (p.Glu1914Lys) variant in MYH7 has been reported in at least 6 individuals with complex cardiomyopathy presentations, including predominantly dilated cardiomyopathy, features of LVNC, and restrictive physiology with early-onset in multiple instances (Lakdawala 2012 PMID: 22464770; Pugh 2014 PMID: 24503780; Lamont 2015 PMID: 20301606; Walsh 2017 PMID: 27532257; Wang 2017 PMID: 28855170; Miura 2019 PMID: 30996762). This variant segregated with disease in 2 affected siblings from 1 family (Miura 2019 PMID: 30996762); however this data is currently insufficient to apply PP1. This variant has been confirmed de novo occurrence in 2 of the above reported individuals with additional features of myopathy (PS2; Lamont 2014 PMID24664454). This variant was absent from large population studies (PM2; http://gnomad.broadinstitute.org, v2.1.1). 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 dilated cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate; PS2; PM2; PP3

Met criteria codes

• PS4_Moderate: SUMMARY: The c.5740G>A (p.Glu1914Lys) variant in MYH7 has been reported in 7 individuals with complex cardiomyopathy presentations, including predominantly dilated cardiomyopathy, features of LVNC, and restrictive physiology with early-onset in multiple instances (Lakdawala 2012 PMID22464770; Pugh 2014 PMID24503780; Lamont 2015 PMID:20301606; Walsh 2017 PMID:27532257; Wang 2017 PMID:28855170; Miura 2019 PMID:30996762). LMM - Seen in 1 proband with DCM (same as Lakdawala 2012, Pugh 2014, and Walsh 2017) Pugh 2014 PMID24503780 - Seen in 1 proband with DCM at LMM (same as Lakdawala) Lakdawala 2012 PMID22464770 - Seen in 1 proband with DCM at LMM GeneDx - Seen in 1 proband with NICM and LVNC s/p heart transplant at 19 yo Walsh 2017 PMID:27532257 - Seen in 1 proband with DCM from OMGL (Paper lists at HCM, but per Kate Thomson the referral was for HCM, but they had a clinical diagnosis of DCM) & 1 proband with DCM from LMM (same as Lakdawala 2012 & Pugh 2014) Lamont 2014 PMID:24664454 - Seen as de novo (parentage confirmed by haplotyping - mentioned in discussion section) in 2 infants with features of DCM and myopathy Lamont 2015 PMID:20301606 - GeneReviews summary, mentions variant and references back to 2014 article Wang 2017 PMID:28855170 - Seen in 1 Japanese proband with LVNC with reduced EF (limited details on participants provided in Supp Table S7) Miura 2019 PMID:30996762 - Seen in 3 siblings with biventricular LVNC and restrictive physiology (need clinician input to confirm phenotype details) PMID: 29624713 - unclear if included, unable to access Martinez 2020 In press (no PMID)
• PS2: This variant has been confirmed de novo occurrence in 2 of the above reported individuals with additional features of myopathy (Lamont 2014 PMID24664454).
• PP3: Alamut tools, except for AlignGVGD, and additional tools below predict damaging. Sarcomere Polyphen predicts PATH. Amino acid is conserved across vertebrates except for Domestic goat, which carries this variant amino acid (Lys), but consistency of all other tools sufficient to apply. REVEL supports damaging.
• PM2: Variant is absent from gnomAD with >30x coverage

Not Met criteria codes

• BS4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS3: No functional data
• BS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS3: 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
• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP1: This variant segregated with disease in 2 affected siblings from 1 family (Miura 2019 PMID30996762); however this data is currently insufficient to apply PP1.
• PM1: Variant is outside head domain (aa 181-937)

Approved on: 2021-03-22

Published on: 2021-08-25