Submissions for variant NM_000256.3(MYBPC3):c.1153G>A (p.Val385Met)

gnomAD frequency: 0.00001  dbSNP: rs772073491

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000206400	SCV000259253	uncertain significance	Hypertrophic cardiomyopathy	2023-12-31	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 385 of the MYBPC3 protein (p.Val385Met). This variant is present in population databases (rs772073491, gnomAD 0.007%). This missense change has been observed in individuals with dilated cardiomyopathy and/or hypertropic cardiomyopathy (PMID: 21750094, 27532257, 31513939, 33782553; Invitae). ClinVar contains an entry for this variant (Variation ID: 219403). 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. 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.
Center for Human Genetics, University of Leuven	RCV000206400	SCV000886819	uncertain significance	Hypertrophic cardiomyopathy	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001184019	SCV001349890	uncertain significance	Cardiomyopathy	2023-05-12	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 385 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown that this variant reduces protein stability in vitro (PMID: 34097875). This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 31513939, 32841044, 33782553) and in an individual affected with dilated cardiomyopathy (PMID: 21750094). This variant has also been reported in three individuals from one family who were affected with dilated cardiomyopathy, acute myocarditis, or asymptomatic, respectively (PMID: 32356610). This variant has been identified in 3/245982 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.
Ambry Genetics	RCV002345726	SCV002623178	uncertain significance	Cardiovascular phenotype	2022-07-27	criteria provided, single submitter	clinical testing	The p.V385M variant (also known as c.1153G>A), located in coding exon 13 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 1153. The valine at codon 385 is replaced by methionine, an amino acid with highly similar properties. This alteration has been reported in various cardiomyopathy cohorts, including dilated cardiomyopathy cohorts and hypertrophic cardiomyopathy cohorts; however, clinical details were limited in some cases and additional alterations were identified in other cardiac-related genes (Waldm&uuml;ller S et al. Eur J Heart Fail, 2011 Nov;13:1185-92; Walsh R et al. Genet Med, 2017 02;19:192-203; Wang L et al. Compr Physiol, 2018 03;8:631-709; Helms AS et al. Circ Genom Precis Med, 2020 10;13:396-405; Piriou N et al. ESC Heart Fail, 2020 May:[ePub ahead of print]; Robyns T et al. Eur J Med Genet, 2020 Mar;63:103754). Additionally, this variant has been reported in the Jackson Heart Study cohort; however, clinical details were limited (Bick AG et al. Am J Hum Genet, 2012 Sep;91:513-9). This amino acid position is well 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.
Fulgent Genetics, Fulgent Genetics	RCV002503799	SCV002796999	uncertain significance	Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10	2021-07-26	criteria provided, single submitter	clinical testing
CSER _CC_NCGL, University of Washington	RCV000206400	SCV000503534	uncertain significance	Hypertrophic cardiomyopathy	2016-08-01	no assertion criteria provided	research	Found in patient having exome sequencing for an unrelated indication. No known history of cardiomyopathy.