Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • See Evidence submitted by expert panel for details.

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

CA012904

164316 (ClinVar)

Gene: MYH7
Condition: dilated cardiomyopathy
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 6106a59d-ad87-4369-8ac2-364ff07935c4
Approved on: 2021-09-27
Published on: 2021-10-01

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
More

Pathogenic

Met criteria codes 6
PS4_Moderate PP1_Strong PP3 PM5 PM6 PM2
Not Met criteria codes 18
PVS1 BS3 BS1 BS4 BS2 BP3 BP7 BP5 BP2 BP4 PS3 PS1 PS2 BA1 PP4 PM4 PM1 PM3

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
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.
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).
PP3
Majority of tools support an impact, while REVEL is at the threshold; Variant is conserved
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
PVS1
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
BS2
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
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
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
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP4
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
Curation History
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