Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Johns Hopkins Genomics, |
RCV001250559 | SCV001425393 | uncertain significance | Freeman-Sheldon syndrome; Arthrogryposis, distal, type 2B3 | 2020-04-03 | criteria provided, single submitter | clinical testing | This MYH3 variant is absent from a large population dataset and has not been reported in ClinVar nor the literature, to our knowledge. Of three bioinformatics tools queried, two predict that the substitution would be damaging, while one predicts that it would be benign. The lysine residue at this position is evolutionarily conserved across all species assessed. Bioinformatic analysis predicts that this missernse variant would not affect normal exon 23 splicing, although this has not been confirmed experimentally to our knowledge. Due to insufficient evidence that this variant is deleterious, we consider the clinical significance of c.2891A>G to be uncertain at this time. |
Invitae | RCV003770297 | SCV004649336 | uncertain significance | not provided | 2023-12-20 | criteria provided, single submitter | clinical testing | This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 964 of the MYH3 protein (p.Lys964Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MYH3-related conditions. ClinVar contains an entry for this variant (Variation ID: 973882). 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 not expected to disrupt MYH3 protein function with a negative 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. |