Submissions for variant NM_002471.4(MYH6):c.3428G>A (p.Arg1143Gln)

dbSNP: rs543585784

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000214617	SCV000272021	uncertain significance	not specified	2015-01-29	criteria provided, single submitter	clinical testing	The p.Arg1143Gln variant in MYH6 has not been previously reported in individuals with cardiomyopathy, but has been identified in 9/15338 South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSN P rs543585784). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Arg1143Gln variant is uncertain.
Ambry Genetics	RCV000620062	SCV000740191	uncertain significance	Cardiovascular phenotype	2022-05-26	criteria provided, single submitter	clinical testing	The p.R1143Q variant (also known as c.3428G>A), located in coding exon 24 of the MYH6 gene, results from a G to A substitution at nucleotide position 3428. The arginine at codon 1143 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported once in a sudden unexplained death cohort (Sanchez O et al. PLoS ONE, 2016 Dec;11:e0167358). 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	RCV001798705	SCV002043183	likely benign	Cardiomyopathy	2020-10-27	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001853464	SCV002216655	uncertain significance	Hypertrophic cardiomyopathy 14	2024-09-04	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1143 of the MYH6 protein (p.Arg1143Gln). This variant is present in population databases (rs543585784, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 27930701, 28611029, 36964972). ClinVar contains an entry for this variant (Variation ID: 228890). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MYH6 protein function with a positive predictive value of 80%. 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355795	SCV001550779	uncertain significance	not provided		no assertion criteria provided	clinical testing	The MYH6 p.Arg1143Gln variant was identified in 2 of 1688 proband chromosomes (frequency: 0.00119) from one individual with cardiovascular disease and another individual with sudden unexplained death (Sanchez_2016_PMID:27930701; Haskell_2017_PMID:28611029). The variant was identified in dbSNP (ID: rs543585784) and ClinVar (classified as VUS by Illumina, Ambry Genetics and Laboratory for Molecular Medicine). The variant was not identified in COSMIC or LOVD 3.0. The variant was identified in control databases in 19 of 239592 chromosomes (0 homozygous) at a frequency of 0.000079 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: South Asian in 13 of 30216 chromosomes (freq: 0.00043), East Asian in 1 of 17930 chromosomes (freq: 0.000056), European (non-Finnish) in 4 of 108002 chromosomes (freq: 0.000037) and Latino in 1 of 34158 chromosomes (freq: 0.000029), but was not observed in the African, Ashkenazi Jewish, European (Finnish) or Other populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Arg1143 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004734864	SCV005363595	uncertain significance	MYH6-related disorder	2024-04-17	no assertion criteria provided	clinical testing	The MYH6 c.3428G>A variant is predicted to result in the amino acid substitution p.Arg1143Gln. This variant was reported in an individual with dilated cardiomyopathy and heart failure (Table S2 - Haskell et al. 2017. PubMed ID: 28611029) and in a case of sudden death (Sanchez et al. 2016. PubMed ID: 27930701). This variant is reported in 0.043% of alleles in individuals of South Asian descent in gnomAD and is interpreted as uncertain significance by most submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/228890/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.