Submissions for variant NM_152263.4(TPM3):c.547C>T (p.Arg183Ter)

dbSNP: rs727504181

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000154017	SCV000203645	pathogenic	not provided	2014-02-03	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002516101	SCV003306504	pathogenic	Congenital myopathy 4B, autosomal recessive; Congenital myopathy with fiber type disproportion	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg183*) in the TPM3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TPM3 are known to be pathogenic (PMID: 10619715, 27858751). This variant is present in population databases (rs727504181, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with TPM3-related conditions. ClinVar contains an entry for this variant (Variation ID: 167744). For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV002514966	SCV003761259	uncertain significance	TPM3-related myopathy	2023-01-25	criteria provided, single submitter	curation	The heterozygous p.Arg183Ter variant in TPM3 was identified by our study in one individual with congenital myopathy. The p.Arg183Ter variant in TPM3 has not been previously reported in the literature in individuals with congenital fiber-type disproportion myopathy but has been identified in 0.0009% (1/113762) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs727504181). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 167744) and has been interpreted as pathogenic by Eurofins NTD LLC. This nonsense variant leads to a premature termination codon at position 183, which is predicted to lead to a truncated or absent protein. Loss of function of the TPM3 gene is strongly associated to autosomal recessive congenital fiber-type disproportion myopathy. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PVS1_Strong, PM2_Supporting (Richards 2015).