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

gnomAD frequency: 0.00001  dbSNP: rs727504502

Total submissions: 8

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
Labcorp Genetics (formerly Invitae), Labcorp	RCV001242440	SCV001415527	uncertain significance	Hypertrophic cardiomyopathy 14	2025-01-27	criteria provided, single submitter	clinical testing	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). This variant is present in population databases (rs727504502, gnomAD 0.006%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 31513939). ClinVar contains an entry for this variant (Variation ID: 178868). 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 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	RCV001559102	SCV001781179	uncertain significance	not provided	2024-05-23	criteria provided, single submitter	clinical testing	Reported in association with cardiomyopathy in published literature; however, no segregation or functional studies were described (PMID: 28082330, 25351510, 31513939); 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: 25351510, 31513939, 38540378, 28082330)
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
PreventionGenetics, part of Exact Sciences	RCV004734734	SCV005364218	uncertain significance	MYH6-related disorder	2024-07-24	no assertion criteria provided	clinical testing	The MYH6 c.5072G>A variant is predicted to result in the amino acid substitution p.Arg1691His. This variant has been reported in individuals with hypertrophic cardiomyopathy (Table S1, Lopes et al. 2015. PubMed ID: 25351510; Table S7, Walsh et al. 2017. PubMed ID: 28082330; Table S2, Robyns et al. 2020. PubMed ID: 31513939). This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD and is interpreted as uncertain significance by multiple submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/178868/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.