Submissions for variant NM_000256.3(MYBPC3):c.3412C>T (p.Arg1138Cys)

gnomAD frequency: 0.00009  dbSNP: rs377171707

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158459	SCV000208394	uncertain significance	not provided	2024-03-01	criteria provided, single submitter	clinical testing	Reported in individuals with HCM referred for genetic testing at GeneDx and in published literature, many of whom harbor additional variants in cardiac disease-related genes (PMID: 23233322, 30959811, 32830170, 33487615); 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: 25637381, 32830170, 33487615, 30959811, 25524337, 23233322)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001058138	SCV001222684	uncertain significance	Hypertrophic cardiomyopathy	2024-12-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1138 of the MYBPC3 protein (p.Arg1138Cys). This variant is present in population databases (rs377171707, gnomAD 0.02%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 23233322, 30959811, 32830170). ClinVar contains an entry for this variant (Variation ID: 161307). 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.
Color Diagnostics, LLC DBA Color Health	RCV001804857	SCV002052127	uncertain significance	Cardiomyopathy	2023-08-24	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 1138 of the MYBPC3 protein. Computational prediction suggests that this variant may have a 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 individuals affected with hypertrophic cardiomyopathy (PMID: 23233322, 32830170) and in an individual affected with myocardial disarray (PMID: 30959811). This variant has been identified in 11/268516 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	RCV002453473	SCV002612758	uncertain significance	Cardiovascular phenotype	2023-02-28	criteria provided, single submitter	clinical testing	The p.R1138C variant (also known as c.3412C>T), located in coding exon 31 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 3412. The arginine at codon 1138 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in hypertrophic cardiomyopathy (HCM) cohorts; however, clinical details were limited (Kassem H et al. J Cardiovasc Transl Res, 2013 Feb;6:65-80; Nakashima Y et al. Circ J, 2020 Sep;84:1846-1853). 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.
Fulgent Genetics, Fulgent Genetics	RCV002492543	SCV002776833	uncertain significance	Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10	2021-09-10	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000158459	SCV003817159	uncertain significance	not provided	2020-12-18	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001058138	SCV004836601	uncertain significance	Hypertrophic cardiomyopathy	2024-06-11	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 1138 of the MYBPC3 protein. Computational prediction suggests that this variant may have a 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 individuals affected with hypertrophic cardiomyopathy (PMID: 23233322, 32830170) and in an individual affected with myocardial disarray (PMID: 30959811). This variant has been identified in 11/268516 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.
CSER _CC_NCGL, University of Washington	RCV000148671	SCV000190395	uncertain significance	Primary familial hypertrophic cardiomyopathy	2014-06-01	no assertion criteria provided	research