Submissions for variant NM_152263.4(TPM3):c.452A>C (p.Glu151Ala)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003780948	SCV004569169	pathogenic	Congenital myopathy 4B, autosomal recessive; Congenital myopathy with fiber type disproportion	2023-09-13	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Glu151 amino acid residue in TPM3. Other variant(s) that disrupt this residue have been observed in individuals with TPM3-related conditions (PMID: 33435938), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects TPM3 function (PMID: 32797717, 33435938). 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 TPM3 protein function. This missense change has been observed in individual(s) with clinical features of autosomal dominant congenital myopathy (PMID: 24692096; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 151 of the TPM3 protein (p.Glu151Ala).