ClinVar Miner

Submissions for variant NM_002470.4(MYH3):c.700G>A (p.Ala234Thr)

gnomAD frequency: 0.00001  dbSNP: rs121913623
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000486376 SCV000567161 pathogenic not provided 2024-06-10 criteria provided, single submitter clinical testing Published functional studies using a Drosophila model demonstrate disrupted myofibril assembly and stability, limited viability, and hindered flight and jump ability of the transgenic flies (PMID: 32799913); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23401156, 22519952, 18695058, 32799913)
Fulgent Genetics, Fulgent Genetics RCV000762979 SCV000893424 likely pathogenic Freeman-Sheldon syndrome; Distal arthrogryposis type 2B1; Contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A 2018-10-31 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000486376 SCV005836592 uncertain significance not provided 2024-02-17 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 234 of the MYH3 protein (p.Ala234Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of distal arthrogryposis (PMID: 18695058). ClinVar contains an entry for this variant (Variation ID: 14145). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MYH3 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.
OMIM RCV000015208 SCV000035465 pathogenic Arthrogryposis, distal, type 2B3 2008-08-01 no assertion criteria provided literature only

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