ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.49C>T (p.Arg17Cys)

gnomAD frequency: 0.00003  dbSNP: rs45511396
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Total submissions: 11
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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 RCV000035944 SCV000059595 uncertain significance not specified 2020-03-13 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg17Cys variant in MYH7 has been identified in 3 individuals with HCM, including a child with an additional variant of uncertain significance in MYH7 in trans (Alfares 2015, Walsh 2017, LMM data). It has also been identified in 0.002% (4/251344) of total (pan-ethnic) chromosomes by gnomAD. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria Applied: PM2, PP3, PS4_Supporting.
Color Diagnostics, LLC DBA Color Health RCV001188090 SCV001355058 uncertain significance Cardiomyopathy 2023-03-23 criteria provided, single submitter clinical testing This missense variant replaces arginine with cysteine at codon 17 of the MYH7 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A study with cardiac ventricular tissue from a carrier showed that this variant increased the proportion of myosins in disordered state compared to super relaxed state conformations (PMID: 31983222). This variant has been reported in a few individuals affected with hypertrophic cardiomyopathy (PMID: 25611685, 27532257, 31983222, 33495597). This variant has been identified in 4/251344 chromosomes 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.
Invitae RCV001370021 SCV001566482 uncertain significance Hypertrophic cardiomyopathy 2023-11-07 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 17 of the MYH7 protein (p.Arg17Cys). This variant is present in population databases (rs45511396, gnomAD 0.003%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 25611685, 27532257). ClinVar contains an entry for this variant (Variation ID: 43050). 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 with a positive predictive value of 95%. 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 RCV001555196 SCV001776570 uncertain significance not provided 2019-11-12 criteria provided, single submitter clinical testing Reported in two patients with HCM in the published literature; detailed clinical information was not provided (Alfares et al., 2015); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 43050; 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 a deleterious effect; This variant is associated with the following publications: (PMID: 25611685, 27532257)
Revvity Omics, Revvity RCV001555196 SCV003817711 uncertain significance not provided 2021-07-22 criteria provided, single submitter clinical testing
Baylor Genetics RCV003320083 SCV003834825 uncertain significance Myosin storage myopathy 2022-12-08 criteria provided, single submitter clinical testing
Baylor Genetics RCV003147323 SCV003835881 uncertain significance Myopathy, myosin storage, autosomal recessive 2022-12-08 criteria provided, single submitter clinical testing
Baylor Genetics RCV003147318 SCV003835957 uncertain significance Dilated cardiomyopathy 1S 2022-12-08 criteria provided, single submitter clinical testing
Baylor Genetics RCV003147321 SCV003836055 uncertain significance MYH7-related skeletal myopathy 2022-12-08 criteria provided, single submitter clinical testing
Baylor Genetics RCV003147322 SCV003836066 uncertain significance Hypertrophic cardiomyopathy 1 2022-12-08 criteria provided, single submitter clinical testing
Baylor Genetics RCV003320083 SCV003836074 uncertain significance Myosin storage myopathy 2022-12-08 criteria provided, single submitter clinical testing

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