ClinVar Miner

Submissions for variant NM_152263.4(TPM3):c.832G>A (p.Ala278Thr)

gnomAD frequency: 0.00001  dbSNP: rs377438824
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001374353 SCV001571178 uncertain significance Congenital myopathy 4B, autosomal recessive; Congenital myopathy with fiber type disproportion 2020-05-21 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with TPM3-related conditions. This variant is present in population databases (rs377438824, ExAC 0.02%). This sequence change replaces alanine with threonine at codon 278 of the TPM3 protein (p.Ala278Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine.
Neuberg Centre For Genomic Medicine, NCGM RCV004762136 SCV005373686 uncertain significance Congenital myopathy 4A, autosomal dominant 2023-05-20 criteria provided, single submitter clinical testing The observed missense variant c.832G>A(p.Ala278Thr) in the TPM3 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is reported with the allele frequency 0.001% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Uncertain Significance. However, no details are available for independent assessment. The amino acid Alanine at position 278 is changed to a Threonine changing protein sequence and it might alter its composition and physico-chemical properties. Computational evidence (MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The residue is conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.

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