Submissions for variant NM_000257.4(MYH7):c.2711G>A (p.Arg904His)

dbSNP: rs397516165

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cardiomyopathy Variant Curation Expert Panel	RCV000208309	SCV001976462	pathogenic	Primary dilated cardiomyopathy	2021-09-27	reviewed by expert panel	curation	The NM_000257.4(MYH7):c.2711G>A (p.Arg904His) variant has been identified in at least 14 individuals with DCM in the literature (PS4; Waldmüller 2011 PMID:21750094; Lakdawala 2012 PMID:22464770; Pugh 2014 PMID:24503780; Chami 2014 PMID:25448463; Walsh 2017 PMID:27532257; Gigli 2019 PMID:31514951; Ambry pers. comm.; GeneDx pers. comm.; Invitae pers. comm.). In 3 of theses cases, the variant was identified as an unconfirmed de novo occurrence (PM6_Strong; Lakdawala 2012 PMID:22464770; GeneDx pers. comm.; OMGL pers. comm.). This variant also segregated with disease in 7 affected individuals with DCM across 4 families (PP1_Strong; Chami 2014 PMID:25448463; GeneDx pers. comm.; OMGL pers. comm.). This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). While this variant lies in the head region of the protein (aa 181-937), where missense variants are statistically more likely to be associated with HCM (Walsh 2017 PMID:27532257), location in this region cannot be used to support pathogenicity for other phenotypes; therefore PM1 is not applicable. Finally, 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 (DCM) in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4, PM6_Strong, PP1_Strong, PM2, PP3.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000208309	SCV000059467	likely pathogenic	Primary dilated cardiomyopathy	2018-03-15	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx	RCV000505767	SCV000208502	pathogenic	not provided	2023-02-27	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21750094, 34935411, 27532257, 25448463, 22464770, 24503780, 31514951, 31983221, 34136434, 35288587, 29300372)
Blueprint Genetics	RCV000208309	SCV000264084	likely pathogenic	Primary dilated cardiomyopathy	2015-03-17	criteria provided, single submitter	clinical testing
Invitae	RCV000550238	SCV000623680	pathogenic	Hypertrophic cardiomyopathy	2023-11-07	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 904 of the MYH7 protein (p.Arg904His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy and dilated cardiomyopathy (PMID: 21750094, 22464770, 25448463, 27532257; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 42926). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYH7 protein function with a positive predictive value of 95%. This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000620255	SCV000737379	pathogenic	Cardiovascular phenotype	2023-05-22	criteria provided, single submitter	clinical testing	The p.R904H pathogenic mutation (also known as c.2711G>A), located in coding exon 21 of the MYH7 gene, results from a G to A substitution at nucleotide position 2711. The arginine at codon 904 is replaced by histidine, an amino acid with highly similar properties. This variant has been detected in multiple individuals with dilated cardiomyopathy (DCM) and was reported as a de novo alteration in several cases (Waldmüller S et al. Eur. J. Heart Fail., 2011 Nov;13:1185-92; Lakdawala NK et al. J. Card. Fail., 2012 Apr;18:296-303; Chami N et al. Can J Cardiol, 2014 Dec;30:1655-61; Walsh R et al. Genet. Med., 2017 02;19:192-203; personal communication; Ambry internal data). In addition, this variant was shown to segregate with DCM in one small family (Chami N et al. Can J Cardiol, 2014 Dec;30:1655-61). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769455	SCV000900849	likely pathogenic	Cardiomyopathy	2016-11-09	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000845382	SCV000987441	pathogenic	Primary familial dilated cardiomyopathy		criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Region Ostergotland	RCV002251732	SCV002522547	pathogenic	Dilated cardiomyopathy 1S	2019-12-19	criteria provided, single submitter	clinical testing	PS4, PM2, PM6, PP3, PP5, PM5
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000505767	SCV001932371	pathogenic	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000505767	SCV001963100	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000505767	SCV002034547	pathogenic	not provided		no assertion criteria provided	clinical testing