Submissions for variant NM_000257.4(MYH7):c.3152C>T (p.Ala1051Val)

gnomAD frequency: 0.00001  dbSNP: rs727504358

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000628879	SCV000749787	uncertain significance	Hypertrophic cardiomyopathy	2022-08-22	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1051 of the MYH7 protein (p.Ala1051Val). This variant is present in population databases (rs727504358, gnomAD 0.01%). This missense change has been observed in individual(s) with dilated cardiomyopathy and/or hypertrophic cardiomyopathy (PMID: 22464770, 28356264, 32894683). ClinVar contains an entry for this variant (Variation ID: 177851). 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 C0"). 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.
Mendelics	RCV000989189	SCV001139413	uncertain significance	Hypertrophic cardiomyopathy 1	2019-05-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001183972	SCV001349831	uncertain significance	Cardiomyopathy	2023-04-25	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 1051 of the MYH7 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 28356264, 32894683) and in an individual affected with dilated cardiomyopathy (PMID: 22464770). This variant has been identified in 7/251476 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
GeneDx	RCV001560656	SCV001783111	uncertain significance	not provided	2020-03-05	criteria provided, single submitter	clinical testing	Observed in a patient with dilated cardiomyopathy (DCM) in the published literature (Lakdawala et al., 2012); Reported as a variant of uncertain significance by other clinical laboratories in ClinVar (ClinVar Variant ID# 177851; Landrum et al., 2016); 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: 22464770)
Ambry Genetics	RCV002321636	SCV002608529	uncertain significance	Cardiovascular phenotype	2021-06-30	criteria provided, single submitter	clinical testing	The p.A1051V variant (also known as c.3152C>T), located in coding exon 23 of the MYH7 gene, results from a C to T substitution at nucleotide position 3152. The alanine at codon 1051 is replaced by valine, an amino acid with similar properties. This variant has been reported in hypertrophic cardiomyopathy and dilated cardiomyopathy cohorts with limited clinical details provided (Lakdawala NK et al. J Card Fail, 2012 Apr;18:296-303; G&oacute;mez J et al. Circ Cardiovasc Genet, 2017 Apr;10:[ePub ahead of print]; Bick AG et al. Proc Natl Acad Sci U S A, 2017 10;114:E9096-E9104). This amino acid position is well conserved in available vertebrate species; however, valine is the reference amino acid in other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154488	SCV000204158	uncertain significance	not specified	2013-01-23	no assertion criteria provided	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory