ClinVar Miner

Submissions for variant NM_002470.4(MYH3):c.1123G>A (p.Glu375Lys)

dbSNP: rs121913621
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
SIB Swiss Institute of Bioinformatics RCV000015206 SCV000998857 uncertain significance Arthrogryposis, distal, type 2B3 2019-08-21 criteria provided, single submitter curation This variant is interpreted as a variant of uncertain significance for Arthrogryposis, distal, 2B3, autosomal dominant. The following ACMG Tag(s) were applied: PM2, PP3, PM1.
GeneDx RCV001650833 SCV001871152 likely pathogenic not provided 2023-10-20 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: 31030430, 19309503, 29625835, 17380469, 16642020, 26578207)
Revvity Omics, Revvity RCV001650833 SCV002017664 pathogenic not provided 2021-02-26 criteria provided, single submitter clinical testing
Invitae RCV001650833 SCV003441669 uncertain significance not provided 2022-06-07 criteria provided, single submitter clinical testing 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 14143). This missense change has been observed in individuals with distal arthrogryposis (PMID: 16642020, 26578207, 31030430). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 375 of the MYH3 protein (p.Glu375Lys).
PreventionGenetics, part of Exact Sciences RCV004532359 SCV004118288 likely pathogenic MYH3-related disorder 2022-10-06 criteria provided, single submitter clinical testing The MYH3 c.1123G>A variant is predicted to result in the amino acid substitution p.Glu375Lys. This variant has been reported in the heterozygous state in at least one family with distal arthrogryposis (reported as 1192G>A, p.Glu375Lys in Toydemir et al. 2006. PubMed ID: 16642020). At PreventionGenetics, we have observed this variant in the heterozygous state in additional individuals with distal arthrogryposis (Internal Data, PreventionGenetics). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic for autosomal dominant distal arthrogryposis.
OMIM RCV000015206 SCV000035463 pathogenic Arthrogryposis, distal, type 2B3 2006-05-01 no assertion criteria provided literature only

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