ClinVar Miner

Submissions for variant NM_002471.4(MYH6):c.2984C>G (p.Thr995Ser)

gnomAD frequency: 0.00003  dbSNP: rs753891816
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001194287 SCV001363689 uncertain significance not specified 2019-04-29 criteria provided, single submitter clinical testing Variant summary: MYH6 c.2984C>G (p.Thr995Ser) results in a conservative amino acid change located in the Myosin tail domain (IPR002928) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.1e-06 in 282846 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2984C>G has been reported in the literature in a heterozygous individuals affected with Atrial Fibrillation (Weeke 2014). This report does not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV001220071 SCV001392044 uncertain significance Hypertrophic cardiomyopathy 14 2024-07-06 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 995 of the MYH6 protein (p.Thr995Ser). This variant is present in population databases (rs753891816, gnomAD 0.002%). This missense change has been observed in individual(s) with atrial fibrillation (PMID: 24120998). ClinVar contains an entry for this variant (Variation ID: 929191). 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 not expected to disrupt MYH6 protein function with a negative 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.
GeneDx RCV001598683 SCV001827791 uncertain significance not provided 2021-01-26 criteria provided, single submitter clinical testing Reported in a patient with lone atrial fibrillation (Weeke et al., 2014); however, detailed clinical information was not provided; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 929191; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24120998)
Ambry Genetics RCV002436766 SCV002750653 uncertain significance Cardiovascular phenotype 2024-09-02 criteria provided, single submitter clinical testing The p.T995S variant (also known as c.2984C>G), located in coding exon 21 of the MYH6 gene, results from a C to G substitution at nucleotide position 2984. The threonine at codon 995 is replaced by serine, an amino acid with similar properties. This alteration has been reported in an atrial fibrillation cohort with limited clinical details (Weeke P et al. Heart Rhythm, 2014 Jan;11:46-52). 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.
Fulgent Genetics, Fulgent Genetics RCV002480643 SCV002787093 uncertain significance Hypertrophic cardiomyopathy 1; Dilated cardiomyopathy 1EE; Hypertrophic cardiomyopathy 14; Atrial septal defect 3; Sick sinus syndrome 3, susceptibility to 2021-08-06 criteria provided, single submitter clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.