Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory for Molecular Medicine, |
RCV001449663 | SCV000199180 | uncertain significance | not specified | 2021-02-02 | criteria provided, single submitter | clinical testing | Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg858Gly variant in MYH7 has been reported in at least 2 individuals with hypertrophic cardiomyopathy (Walsh 2017 PMID: 27532257, LMM data), but was absent from large population studies. This variant lies in the head region of the protein and missense variants in this region are statistically more likely to be disease-associated (Walsh 2017 PMID: 27532257). In addition, several other changes at this position have been identified in individuals with HCM, at least one of which (p.Arg858Cys) meets criteria to be classified as pathogenic. Although this information suggests that changes to this position may not be tolerated, computational prediction tools do not provide strong support for an impact of the p.Arg858Gly variant on the protein. In summary, while there is suspicion for a pathogenic role, the clinical significance of this variant is uncertain due to limited available proband data. ACMG/AMP Criteria applied: PM1, PM5, PM2_Supporting, PS4_Supporting. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000588789 | SCV000696343 | uncertain significance | not provided | 2016-03-09 | criteria provided, single submitter | clinical testing | Variant summary: Variant affects a non-conserved nucleotide and results in a replacement of a large size and basic Arginine (R) with a small size and hydrophobic Glycine (G). 3/5 in silico tools predict the variant to be neutral. It is absent from the large and broad cohorts of the ExAC project. Studies assessing the effect of the variant on protein function were not published at the time of scoring. Variants affecting the same codon, c.2572C>T p.R858C (DM); c.2572C>G p.R858C, c.2572C>A p.R858S (DM); c.2573G>A p.R858H (DM), c.2573G>A p.R858H (DM) are listed in HGMD as Disease Mutation indicating the variant to be located in a mutational hotspot and and suggesting a particular functional importance of residue 858. A clinical diagnostic laboratory classified variant as Uncertain via ClinVar. Considering all, because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance until more information becomes available. |
Invitae | RCV000698652 | SCV000827332 | likely pathogenic | Hypertrophic cardiomyopathy | 2024-01-19 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 858 of the MYH7 protein (p.Arg858Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 23549607, 27247418, 27532257). ClinVar contains an entry for this variant (Variation ID: 164325). 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%. This variant disrupts the p.Arg858 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15358028, 24093860, 28498465). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
Gene |
RCV000588789 | SCV002097413 | likely pathogenic | not provided | 2023-08-09 | criteria provided, single submitter | clinical testing | 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: 27247418, 27532257, 23403236, 23690394, 23549607, 29300372, 25228707) |