Submissions for variant NM_000257.4(MYH7):c.4838G>A (p.Arg1613Lys)

dbSNP: rs397516230

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035935	SCV000059586	uncertain significance	not specified	2013-08-22	criteria provided, single submitter	clinical testing	The Arg1613Lys variant in MYH7 has been identified by our laboratory in 1 Caucas ian individual with DCM, and was not identified in large population studies. Com putational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. Additional information is needed to fully assess the clinical signi ficance of the Arg1613Lys variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000456855	SCV000546235	uncertain significance	Hypertrophic cardiomyopathy	2022-11-28	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MYH7-related conditions. ClinVar contains an entry for this variant (Variation ID: 43041). 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 MYH7 protein function. 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. This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 1613 of the MYH7 protein (p.Arg1613Lys).
GeneDx	RCV000767039	SCV000620438	uncertain significance	not provided	2022-12-15	criteria provided, single submitter	clinical testing	Reported in association with HCM in published literature (Ingles et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30681346)
All of Us Research Program, National Institutes of Health	RCV003996214	SCV004814601	uncertain significance	Cardiomyopathy	2023-03-04	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV003996214	SCV006064895	uncertain significance	Cardiomyopathy	2024-06-12	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with lysine at codon 1613 of the MYH7 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MYH7-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
PreventionGenetics, part of Exact Sciences	RCV004757113	SCV005357635	uncertain significance	MYH7-related disorder	2024-08-27	no assertion criteria provided	clinical testing	The MYH7 c.4838G>A variant is predicted to result in the amino acid substitution p.Arg1613Lys. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. Of note, adjacent variants (p.Glu1610Lys, p.Glu1610Gln, p.Ala1611Val, p.Leu1612Pro) have been reported in patients with cardiomyopathy and muscular dystrophy (Lamont et al. 2014. PubMed ID: 24664454; Marston et al. 2015. PubMed ID: 26406308; Rupp et al. 2018. PubMed ID: 30105547; Supplemental Table 4, Töpf et al. 2020. PubMed ID: 32528171). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.