Variant: NM_000257.4(MYH7):c.2710C>T (p.Arg904Cys)

CA012904

164316 (ClinVar)

Gene: MYH7

Condition: dilated cardiomyopathy

Inheritance Mode: Autosomal dominant inheritance

UUID: 6106a59d-ad87-4369-8ac2-364ff07935c4

HGVS expressions

NM_000257.4:c.2710C>T
NM_000257.4(MYH7):c.2710C>T (p.Arg904Cys)
NC_000014.9:g.23424119G>A
CM000676.2:g.23424119G>A
NC_000014.8:g.23893328G>A
CM000676.1:g.23893328G>A
NC_000014.7:g.22963168G>A
NG_007884.1:g.16543C>T
ENST00000355349.4:c.2710C>T
ENST00000355349.3:c.2710C>T
NM_000257.3:c.2710C>T

Pathogenic

• Met criteria codes: PS4_Moderate PP3 PP1_Strong PM5 PM6 PM2

• Not Met criteria codes: BS2 BS3 BS1 BS4 BP7 BP5 BP2 BP4 BP3 PVS1 PS3 PS1 PS2 PP4 BA1 PM4 PM1 PM3

Expert Panel

Cardiomyopathy VCEP

Criteria Specification Information

Evidence submitted by expert panel

Cardiomyopathy VCEP

The NM_000257.4:c.2710C>T (p.Arg904Cys) variant in MYH7 has been identified in 4 individuals with DCM in the literature (1 of whom also had LVNC; van Spaendonck-Zwarts 2013 PMID:23349452; van der Zwaag 2011 PMID:20573160; Walsh 2017 PMID:27532257; Miller 2017 PMID29212898) and 3 individuals with LVNC (2 of which were pediatric; Yang 2014 PMID:25326635; Wang 2017 PMID:28855170; van Waning 2018 PMID:29447731). This variant was identified in 8 individuals with DCM and 1 proband with LVNC by clinical laboratories (GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.; OMGL pers comm.). Only probands with DCM are counted towards PS4 (n=12; PS4_Moderate). This variant segregated with DCM in 15 affected individuals from 4 families (PP1_Strong; van der Zwaag 2011 PMID:20573160; GeneDx pers. comm.; LMM pers. comm.; OMGL pers. comm.) and was assumed de novo in 1 of the above cases (PM6; GeneDx pers. comm.). This variant has been identified in 0.010% (1/10080) of Ashkenazi Jewish chromosomes by gnomAD v2.1.1 (https://gnomad.broadinstitute.org), but was absent from all other populations. A different pathogenic missense variant has been previously identified at this codon, which indicates that this residue may be critical to the function of the protein (PM5; c.2711G>A p.Arg904His - Variation ID 42926). 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 dilated cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate, PP1_Strong, PM6, PM2, PM5, PP3.

Met criteria codes

• PS4_Moderate: Variant has been identified in 4 individuals with DCM in the literature (van Spaendonck-Zwarts 2013 PMID:23349452; van der Zwaag 2011 PMID:20573160; Walsh 2017 PMID:27532257; Miller 2017 PMID29212898) and 3 individuals with LVNC (2 of which were pediatric; Yang 2014 PMID:25326635; Wang 2017 PMID:28855170; van Waning 2018 PMID:29447731). This variant was identified in 8 individuals with DCM (3 of whom had VUS in other genes) and 1 proband with LVNC by clinical laboratories (GeneDx pers. comm.; Invitae pers. comm.; LMM pers. comm.; OMGL pers comm.) Ignore entries from Neel Gadhorke (from other assessment), as articles were re-entered and therefore counts are being double counted.
• PP3: Majority of tools support an impact, while REVEL is at the threshold; Variant is conserved
• PP1_Strong: Total of 15 segregations from 4 families. Van der Zwaag et al (2011 PMID: 20573160) report a DCM family with 9 total segregations and then 6 additional segregations from internal data (LMM, OMGL, GeneDx).
• PM5: p.Arg904Pro - 1* VUS in ClinVar; Not in HGMD p.Arg904His - 2* P/LP in ClinVar; Re-evaluated and is PATHOGENIC by VCEP
• PM6: 1 assumed de novo occurrence; parents of an LMM proband tested at GeneDx and were negative
• PM2: This variant was identified in 0.010% (1/10080) of Ashkenazi Jewish chromosomes by gnomAD v2.1.1 (https://gnomad.broadinstitute.org); although only 1 allele was identified, and was absent from all other populations

Not Met criteria codes

• BS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS3: No evidence
• BS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP7: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP2: 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
• BP3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PVS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS3: No evidence
• PS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS2: No evidence
• PP4: 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
• PM4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM1: Located in MYH7 head domain, but evidence is for DCM and so this rule cannot be applied
• PM3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Approved on: 2021-09-27

Published on: 2021-10-01