Submissions for variant NM_152263.4(TPM3):c.503G>T (p.Arg168Leu)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003796898	SCV004585919	uncertain significance	Congenital myopathy 4B, autosomal recessive; Congenital myopathy with fiber type disproportion	2023-03-07	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. This variant disrupts the p.Arg168 amino acid residue in TPM3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12467750, 17376686, 21357678, 22749829). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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) performed at Invitae indicates that this missense variant is expected to disrupt TPM3 protein function. This missense change has been observed in individual(s) with nemaline myopathy (PMID: 33084218). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 168 of the TPM3 protein (p.Arg168Leu).