ClinVar Miner

Submissions for variant NM_003289.4(TPM2):c.463G>A (p.Ala155Thr)

dbSNP: rs1563929039
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000690257 SCV000817938 pathogenic Arthrogryposis, distal, type 1A 2024-04-08 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 155 of the TPM2 protein (p.Ala155Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with distal arthrogryposis (PMID: 31966463, 33060286, 35052370, 35579956). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 569587). 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 TPM2 protein function. Experimental studies have shown that this missense change affects TPM2 function (PMID: 35579956). For these reasons, this variant has been classified as Pathogenic.
DASA RCV002051885 SCV002318964 likely pathogenic TPM2-related cap myopathy 2022-03-25 criteria provided, single submitter clinical testing The c.463G>A;p.(Ala155Thr) missense change has been observed in affected individual(s) (PMID: 31966463)-PS4_moderate. This variant is not present in population databases (rs1563929039- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br.) - PM2. Pathogenic missense variant in this residue have been reported (PMID: 22832343) - PM5. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is likely pathogenic
GeneDx RCV002249410 SCV002520180 likely pathogenic not provided 2022-04-11 criteria provided, single submitter clinical testing 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); Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 30544720, 29792862, 28939420, 31155291, 32087052, 22832343, McAdow2021[article-not certified by peer review], 33060286, 23413262, Neissi2022[CaseReport], 31966463, 35052370)
Institute of Human Genetics, University of Leipzig Medical Center RCV000690257 SCV004027710 pathogenic Arthrogryposis, distal, type 1A 2023-07-25 criteria provided, single submitter clinical testing Criteria applied: PS3,PS2,PS4_MOD,PM1,PM5,PM2_SUP

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