Total submissions: 8
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Labcorp Genetics |
RCV000230889 | SCV000287438 | uncertain significance | Hypertrophic cardiomyopathy 14 | 2024-01-25 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 1826 of the MYH6 protein (p.Gly1826Asn). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with MYH6-related conditions (PMID: 15998695, 27600940). ClinVar contains an entry for this variant (Variation ID: 239179). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The asparagine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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. |
Ambry Genetics | RCV000253607 | SCV000319750 | likely benign | Cardiovascular phenotype | 2019-11-08 | criteria provided, single submitter | clinical testing | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. |
CHEO Genetics Diagnostic Laboratory, |
RCV000770424 | SCV000901867 | likely benign | Cardiomyopathy | 2019-07-23 | criteria provided, single submitter | clinical testing | |
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, |
RCV000845389 | SCV000987450 | uncertain significance | Conduction disorder of the heart | criteria provided, single submitter | clinical testing | ||
Gene |
RCV001658058 | SCV001873720 | uncertain significance | not provided | 2024-07-17 | criteria provided, single submitter | clinical testing | Reported in association with cardiomyopathy in published literature, although some patients harbor additional cardiogenetic variants (also described as c.25743_25744delGGinsAA due to alternative nomenclature) (PMID: 20215591, 27600940, 32603605); Identified in a patient with non-syndromic congenital heart disease (CHD) (PMID: 29332214); In silico analysis indicates that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27600940, 15998695, 22337857, 23396983, 32492895, 32603605, 29332214, 20215591) |
Victorian Clinical Genetics Services, |
RCV000230889 | SCV002766808 | likely benign | Hypertrophic cardiomyopathy 14 | 2022-02-02 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as likely benign. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - This deletion insertion variant is predicted to result in a missense amino acid change from a glycine to an asparagine (exon 36). (N) 0251 - Variant is heterozygous. (N) 0303 - Variant is present in gnomAD (v3) >=0.01 enriched in the Amish sub-population for a dominant condition (54 heterozygotes, 0 homozygotes). (B) 0309 - Alternative amino acid changes at the same position have been observed in gnomAD (v3) (2 heterozygotes, 0 homozygotes). (N) 0504 - Same amino acid change has been observed in mammals. (B) 0600 - Variant is located in an annotated domain or motif (myosin tail domain; NCBI, PDB). (N) 0708 - Comparable variants have conflicting previous evidence for pathogenicity. Alternative changes at the same residue, to aspartic acid and serine, have previously been reported as pathogenic, VUS and likely benign in patients with cardiomyopathies and atrial septal defect; however it is unclear whether these previous reports represent single discrete variants, or a combination of two nucleotide changes in cis, resulting in the same change to asparagine (ClinVar, LOVD, PMID: 23396983, PMID: 29332214). (N) 0808 - Previous reports of pathogenicity are conflicting. The variant has previously been reported as pathogenic, a VUS, likely benign and as a rare SNP in cardiomyopathy patients (ClinVar, HGMD, LOVD, PMID: 15998695, PMID: 27600940). (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign |
University of Washington Center for Mendelian Genomics, |
RCV001543371 | SCV001761929 | uncertain significance | Primary dilated cardiomyopathy | no assertion criteria provided | research | ||
Prevention |
RCV004532872 | SCV004714243 | uncertain significance | MYH6-related disorder | 2024-02-06 | no assertion criteria provided | clinical testing | The MYH6 c.5476_5477delinsAA variant is predicted to result in an in-frame deletion and insertion. This variant was reported in unrelated individuals with dilated or hypertrophic cardiomyopathy (Carniel et al. 2005. PubMed ID: 15998695; described as p.Gly1826Ser and p.Gly1826Asp as a complex genotype in Table S4, Lopes et al. 2013. PubMed ID: 23396983; described as p.Asp1826Asn, Hershberger et al. 2010. PubMed ID: 20215591; Kim et al. 2020. PubMed ID: 32492895; Cowan et al. 2020. PubMed ID: 32603605). This variant, along with a second MYH6 variant, was also detected in an individual with hypertrophic cardiomyopathy (Cecconi et al. 2016. PubMed ID: 27600940). In gnomAD, the c.5476_5477delinsAA variant appears as two separate allele calls (c.5476G>A and c.5477G>A), and the two variants are documented to occur in cis (on the same allele) in over fifty heterozygous individuals (https://gnomad.broadinstitute.org/variant/14-23853739-CC-TT?dataset=gnomad_r2_1). At this time the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. |