Submissions for variant NM_000257.4(MYH7):c.2863G>A (p.Asp955Asn)

dbSNP: rs886039204

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000251778	SCV000320640	likely pathogenic	Cardiovascular phenotype	2022-07-15	criteria provided, single submitter	clinical testing	The p.D955N variant (also known as c.2863G>A), located in coding exon 21 of the MYH7 gene, results from a G to A substitution at nucleotide position 2863. The aspartic acid at codon 955 is replaced by asparagine, an amino acid with highly similar properties. This variant along with MYH7 p.D545N in cis reportedly co-segregated with disease in families with dilated cardiomyopathy (DCM) and left ventricular non-compaction (Hoedemaekers YM et al. Eur Heart J. 2007;28(22):2732-7; van den Berg MP et al. Eur J Heart Fail. 2010;12(12):1297-9). Both p.D545N and p.D955N were detected in another LVNC cohort; however, additional details were limited (Chang B. Mol Genet Metab. 2011 Feb;102(2):200-6). This alteration also segregated with the TNNT2 p.N83H variant in multiple members of a consanguineous family with DCM; individuals with either variant alone were unaffected (Petropoulou E et al. Eur J Med Genet, 2017 Sep;60:485-488). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic when in cis with MYH7 p.D545N; however, the clinical significance of the p.D955N variant alone is unclear.
Invitae	RCV000552105	SCV000623686	uncertain significance	Hypertrophic cardiomyopathy	2022-05-10	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 955 of the MYH7 protein (p.Asp955Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with left ventricular noncompaction or dilated cardiomyopathy (PMID: 20965760, 23349452, 29447731). ClinVar contains an entry for this variant (Variation ID: 264608). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C15"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV001529965	SCV002013666	uncertain significance	not provided	2022-10-26	criteria provided, single submitter	clinical testing	Identified in patients with cardiomyopathy in published literature; however, all probands were found to harbor other variants in MYH7 or another cardiomyopathy-associated gene (Hoedemaekers et al., 2007; vanSpaendonck-Zwarts et al., 2013; Petropoulou et al., 2017; van Waning et al., 2018); 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: 17947214, 23349452, 29447731, 28642161, 25332820, 20952769, 30650640, 20965760)
Mayo Clinic Laboratories, Mayo Clinic	RCV001529965	SCV004226499	uncertain significance	not provided	2023-04-14	criteria provided, single submitter	clinical testing	PM2_supporting
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001529965	SCV001744363	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001529965	SCV001924777	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001529965	SCV001971399	pathogenic	not provided		no assertion criteria provided	clinical testing