ClinVar Miner

Submissions for variant NM_002471.4(MYH6):c.4264C>T (p.Arg1422Trp)

gnomAD frequency: 0.00010  dbSNP: rs200465713
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000647038 SCV000768825 uncertain significance Hypertrophic cardiomyopathy 14 2023-11-11 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1422 of the MYH6 protein (p.Arg1422Trp). This variant is present in population databases (rs200465713, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with MYH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 537942). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute RCV001256806 SCV001433261 uncertain significance Hypertrophic cardiomyopathy 1 2019-02-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001544894 SCV001471493 uncertain significance not provided 2020-06-23 criteria provided, single submitter clinical testing The MYH6 c.4264C>T; p.Arg1422Trp variant (rs200465713), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 537942). This variant is found in the South Asian population with an allele frequency of 0.033% (10/30616 alleles) in the Genome Aggregation Database. The arginine at codon 1422 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Due to limited information, the clinical significance of the p.Arg1422Trp variant is uncertain at this time.
GeneDx RCV001544894 SCV001764115 uncertain significance not provided 2021-10-29 criteria provided, single submitter clinical testing Reported in association with cardiomyopathy (van Lint et al., 2019); however, specific clinical information was not provided; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 537942; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 26582918, 30847666)
Ambry Genetics RCV002331211 SCV002627783 uncertain significance Cardiovascular phenotype 2020-05-27 criteria provided, single submitter clinical testing The p.R1422W variant (also known as c.4264C>T), located in coding exon 28 of the MYH6 gene, results from a C to T substitution at nucleotide position 4264. The arginine at codon 1422 is replaced by tryptophan, an amino acid with dissimilar properties. This variant has been detected in a from cardiomyopathy cohort with limited detail (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). 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.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV003224365 SCV003920242 uncertain significance Dilated cardiomyopathy 1EE; Hypertrophic cardiomyopathy 14; Atrial septal defect 3; Sick sinus syndrome 3, susceptibility to 2021-03-30 criteria provided, single submitter clinical testing MYH6 NM_002471.3 exon 30 p.Arg1422Trp (c.4264C>T): This variant has not been reported in the literature and is present in 0.03% (10/30616) of South Asian alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/14-23857459-G-A). This variant is present in ClinVar (Variation ID:537942). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Dept of Medical Biology, Uskudar University RCV003318382 SCV004022029 uncertain significance Long QT syndrome 2024-01-08 criteria provided, single submitter research Criteria: PP3

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