ClinVar Miner

Submissions for variant NM_002471.4(MYH6):c.5072G>A (p.Arg1691His)

gnomAD frequency: 0.00001  dbSNP: rs727504502
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000155640 SCV000205348 uncertain significance not specified 2013-04-09 criteria provided, single submitter clinical testing The Arg1691His variant in MYH6 has not been reported in the literature nor previ ously identified by our laboratory. This variant has not been identified in larg e European American and African American populations by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS), though it may be present in other populations. Computational analyses (biochemical amino acid properties, conserv ation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or agai nst an impact to the protein. At this time, additional studies are needed to ful ly assess the clinical significance of this variant.
Center for Human Genetics, University of Leuven RCV000768517 SCV000886830 uncertain significance Hypertrophic cardiomyopathy 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV001242440 SCV001415527 uncertain significance Hypertrophic cardiomyopathy 14 2023-09-17 criteria provided, single submitter clinical testing 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. 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. ClinVar contains an entry for this variant (Variation ID: 178868). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 31513939). This variant is present in population databases (rs727504502, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1691 of the MYH6 protein (p.Arg1691His).
GeneDx RCV001559102 SCV001781179 uncertain significance not provided 2022-02-07 criteria provided, single submitter clinical testing Reported in association with cardiomyopathy in published literature (Lopes et al., 2015; Walsh et al., 2017; Robyns et al., 2020); however, no segregation or functional studies were described; 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; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 178868); This variant is associated with the following publications: (PMID: 28082330, 25351510, 31513939)
AiLife Diagnostics, AiLife Diagnostics RCV001559102 SCV002501860 uncertain significance not provided 2021-08-03 criteria provided, single submitter clinical testing
Ambry Genetics RCV002336331 SCV002642889 uncertain significance Cardiovascular phenotype 2022-06-06 criteria provided, single submitter clinical testing The p.R1691H variant (also known as c.5072G>A), located in coding exon 32 of the MYH6 gene, results from a G to A substitution at nucleotide position 5072. The arginine at codon 1691 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in hypertrophic cardiomyopathy (HCM) cohorts; however, clinical details were limited (Lopes LR et al. Heart, 2015 Feb;101:294-301; Robyns T et al. Eur J Med Genet, 2020 Mar;63:103754). 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 RCV002484940 SCV002787261 uncertain significance Hypertrophic cardiomyopathy 1; Dilated cardiomyopathy 1EE; Hypertrophic cardiomyopathy 14; Atrial septal defect 3; Sick sinus syndrome 3, susceptibility to 2021-07-26 criteria provided, single submitter clinical testing

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