Submissions for variant NM_000258.3(MYL3):c.187C>T (p.Arg63Cys)

gnomAD frequency: 0.00002  dbSNP: rs565312070

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154591	SCV000204264	uncertain significance	not specified	2013-02-13	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Ambry Genetics	RCV000617865	SCV000737020	uncertain significance	Cardiovascular phenotype	2024-07-18	criteria provided, single submitter	clinical testing	The p.R63C variant (also known as c.187C>T), located in coding exon 3 of the MYL3 gene, results from a C to T substitution at nucleotide position 187. The arginine at codon 63 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in hypertrophic cardiomyopathy cohorts (Chiou KR et al. J Cardiol, 2015 Mar;65:250-6; Walsh R et al. Genet Med, 2017 Feb;19:192-203; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309; Harper AR et al. Nat Genet, 2021 Feb;53:135-142). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000777995	SCV000914102	uncertain significance	Cardiomyopathy	2022-09-12	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 63 of the MYL3 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 individuals affected with hypertrophic cardiomyopathy (PMID: 25086479, 27532257). This variant has been identified in 4/251464 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001358941	SCV001554798	uncertain significance	Hypertrophic cardiomyopathy	2023-12-13	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 63 of the MYL3 protein (p.Arg63Cys). This variant is present in population databases (rs565312070, gnomAD 0.003%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 25086479, 27532257, 30847666). ClinVar contains an entry for this variant (Variation ID: 177931). 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.
All of Us Research Program, National Institutes of Health	RCV001358941	SCV004843357	uncertain significance	Hypertrophic cardiomyopathy	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 63 of the MYL3 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 individuals affected with hypertrophic cardiomyopathy (PMID: 25086479, 27532257). This variant has been identified in 4/251464 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.
Clinical Genetics, Academic Medical Center	RCV001699044	SCV001925283	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001699044	SCV001927196	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001699044	SCV001953451	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001699044	SCV001969333	uncertain significance	not provided		no assertion criteria provided	clinical testing