Submissions for variant NM_000258.3(MYL3):c.281G>A (p.Arg94His)

gnomAD frequency: 0.00001  dbSNP: rs199474703

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000824445	SCV000059672	likely pathogenic	Hypertrophic cardiomyopathy	2017-12-15	criteria provided, single submitter	clinical testing	The p.Arg94His variant in MYL3 has been identified in 8 individuals with HCM and segregated with disease in 10 affected relatives across these families (Fokstue n 2008, Zou 2013, Nomura 2016, LMM data). This variant has also been identified in 1/111666 of European chromosomes and 1/33582 Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1994747 03). Computational tools suggest that this variant does not impact the protein b ut these data are not predictive enough to rule out pathogenicity and do not out weigh the above evidence supporting pathogenicity. In summary, although addition al studies are required to fully establish its clinical significance, the p.Arg9 4His variant is likely pathogenic. ACMG/AMP Criteria applied: PP1_Strong; PM2; P S4_Moderate; BP4.
GeneDx	RCV000024468	SCV000208878	likely pathogenic	not provided	2022-04-19	criteria provided, single submitter	clinical testing	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: 26443374, 18409188, 23283745, 27532257, 29398688, 27535533, 34638741)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769168	SCV000900543	likely pathogenic	Cardiomyopathy	2017-01-23	criteria provided, single submitter	clinical testing
Invitae	RCV000824445	SCV000965343	pathogenic	Hypertrophic cardiomyopathy	2023-04-28	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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 tolerated. ClinVar contains an entry for this variant (Variation ID: 31777). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 18409188, 23283745, 26443374, 27532257, 29398688). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs199474703, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 94 of the MYL3 protein (p.Arg94His).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001290568	SCV001478644	pathogenic	Primary familial hypertrophic cardiomyopathy	2021-01-26	criteria provided, single submitter	clinical testing	Variant summary: MYL3 c.281G>A (p.Arg94His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251298 control chromosomes. c.281G>A has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (e.g. Fokstuen_2008, Zou_2013, Walsh_2017). These data indicate that the variant is very likely to be associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV003162261	SCV003901257	likely pathogenic	Cardiovascular phenotype	2023-01-13	criteria provided, single submitter	clinical testing	The p.R94H variant (also known as c.281G>A), located in coding exon 3 of the MYL3 gene, results from a G to A substitution at nucleotide position 281. The arginine at codon 94 is replaced by histidine, an amino acid with highly similar properties. This variant has been detected in several unrelated individuals with hypertrophic cardiomyopathy (HCM) and segregated with HCM in two families in which it appeared to arise from a common ancestor (Fokstuen S et al. Hum Mutat, 2008 Jun;29:879-85; Nomura A et al. J Cardiol, 2016 Feb;67:133-9; Walsh R et al. Genet Med, 2017 02;19:192-203). This variant has also been seen in individuals with HCM who had variants in other cardiomyopathy-related genes (Zou Y et al. Mol Biol Rep, 2013 Jun;40:3969-76; Lopes LR et al. Amyloid, 2019 Dec;26:243-247). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Leiden Muscular Dystrophy (MYL3)	RCV000024468	SCV000045771	not provided	not provided	2012-03-18	no assertion provided	curation
Department of Cardiovascular and Internal Medicine, Kanazawa University Graduate School of Medicine	RCV000491596	SCV000579494	pathogenic	Hypertrophic cardiomyopathy 8	2015-08-01	no assertion criteria provided	research