Submissions for variant NM_000257.4(MYH7):c.2858A>T (p.Asp953Val)

dbSNP: rs730880901

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158855	SCV000208790	pathogenic	not provided	2012-02-10	criteria provided, single submitter	clinical testing	This mutation is denoted Asp953Val (aka D953V) at the protein level and c.2858 A>T at the cDNA level. The Asp953Val mutation in the MYH7 gene has not been previously reported as a disease-causing mutation or as a benign polymorphism, to our knowledge. However a mutation in the same codon, (Asp953His) (Van Driest SL et al. 2004) and mutations in nearby codons (Glu949Lys, Leu961Arg) have been reported in association with HCM, supporting the functional importance of this residue and this region of the protein. Asp953Val results in a non-conservative amino acid substitution of a negatively charged Aspartic acid residue with a non-polar Valine residue. Furthermore, the NHLBI ESP Exome Variant Server reports Asp953Val was not observed in approximately 5,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. The variant is found in HCM panel(s).
Invitae	RCV000226190	SCV000284271	uncertain significance	Hypertrophic cardiomyopathy	2022-03-18	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 953 of the MYH7 protein (p.Asp953Val). This variant is present in population databases (rs730880901, gnomAD 0.0009%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (HCM) (PMID: 27247418). ClinVar contains an entry for this variant (Variation ID: 181380). 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 C65"). 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.
Ambry Genetics	RCV002433705	SCV002749920	uncertain significance	Cardiovascular phenotype	2022-10-06	criteria provided, single submitter	clinical testing	The p.D953V variant (also known as c.2858A>T), located in coding exon 21 of the MYH7 gene, results from an A to T substitution at nucleotide position 2858. The aspartic acid at codon 953 is replaced by valine, an amino acid with highly dissimilar properties. This alteration has been reported in a hypertrophic cardiomyopathy (HCM) cohort (Homburger JR et al. Proc. Natl. Acad. Sci. U.S.A., 2016 06;113:6701-6). Another alteration affecting the same amino acid, p.D953H (c.2857G>C), has also been reported in association with HCM (Van Driest SL et al. J. Am. Coll. Cardiol., 2004 Aug;44:602-10). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Mayo Clinic Laboratories, Mayo Clinic	RCV000158855	SCV004226500	uncertain significance	not provided	2023-02-22	criteria provided, single submitter	clinical testing	PP3, PM2
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000223789	SCV000280336	uncertain significance	not specified	2012-06-04	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Asp953Val (c.2858 A>T, D953V). The variant is novel. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. The aspartate at codon 953 is completely conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at this codon (p.Asp953His) and nearby codons (p.Glu949Lys, p.Leu961Arg). In total the variant has not been seen in ~6700 published controls and publicly available population datasets. There is no variation at codon 953 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of 6/11/13). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 6/11/13).