Submissions for variant NM_000257.4(MYH7):c.2783A>T (p.Asp928Val)

dbSNP: rs727504558

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158852	SCV000208787	likely pathogenic	not provided	2019-08-02	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27247418, 19666645, 31323898)
Invitae	RCV001306502	SCV001495877	likely pathogenic	Hypertrophic cardiomyopathy	2022-11-29	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 181379). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Asp928 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12974739, 15856146, 20038417, 27532257). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 19666645, 27247418, 31323898). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 928 of the MYH7 protein (p.Asp928Val).
Ambry Genetics	RCV002433704	SCV002748255	uncertain significance	Cardiovascular phenotype	2017-09-06	criteria provided, single submitter	clinical testing	The p.D928V variant (also known as c.2783A>T), located in coding exon 21 of the MYH7 gene, results from an A to T substitution at nucleotide position 2783. The aspartic acid at codon 928 is replaced by valine, an amino acid with highly dissimilar properties. This alteration has been reported in individuals with hypertrophic cardiomyopathy (HCM) (Michels M. Eur. Heart J. 2009 Nov;30(21):2593-8). Other alterations affecting this amino acid (p.D928A, p.D928G, and p.D928N) have been reported in individuals with HCM (Erdmann J et al. Clin Genet. 2003 Oct;64(4):339-49; Lopes LR et al. Heart, 2015 Feb;101:294-301; Walsh R et al. Genet. Med., 2017 Feb;19:192-203). 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.
Clinical Genetics, Academic Medical Center	RCV000158852	SCV001921701	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000158852	SCV001928141	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000158852	SCV001971943	likely pathogenic	not provided		no assertion criteria provided	clinical testing