Submissions for variant NM_000256.3(MYBPC3):c.566T>A (p.Val189Asp)

dbSNP: rs397516060

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766312	SCV000208230	uncertain significance	not provided	2022-12-22	criteria provided, single submitter	clinical testing	Identified in an individual with hypertrophic cardiomyopathy in published literature (Walsh et al., 2017); 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: 27532257)
Ambry Genetics	RCV000622174	SCV000740212	uncertain significance	Cardiovascular phenotype	2020-01-28	criteria provided, single submitter	clinical testing	The p.V189D variant (also known as c.566T>A), located in coding exon 5 of the MYBPC3 gene, results from a T to A substitution at nucleotide position 566. The valine at codon 189 is replaced by aspartic acid, an amino acid with highly dissimilar properties. This alteration has been reported in a hypertrophic cardiomyopathy clinical genetic testing cohort; however, clinical details were limited (Walsh R et al. Genet. Med., 2017 Feb;19:192-203). This amino acid position is highly conserved in available 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769359	SCV000900747	uncertain significance	Cardiomyopathy	2023-05-03	criteria provided, single submitter	clinical testing
Invitae	RCV001203662	SCV001374836	uncertain significance	Hypertrophic cardiomyopathy	2023-05-17	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 42773). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257). This sequence change replaces valine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 189 of the MYBPC3 protein (p.Val189Asp). 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive.
Color Diagnostics, LLC DBA Color Health	RCV000769359	SCV002052926	uncertain significance	Cardiomyopathy	2021-04-14	criteria provided, single submitter	clinical testing	This missense variant replaces valine with aspartic acid at codon 189 of the MYBPC3 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with hypertrophic cardiomyopathy (PMID: 27532257). This variant has been identified in 1/245332 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035649	SCV000059300	uncertain significance	not specified	2008-03-01	no assertion criteria provided	clinical testing