Submissions for variant NM_152263.4(TPM3):c.502C>G (p.Arg168Gly)

dbSNP: rs121964854

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Genetic Medicine Research, Children's National Medical Center	RCV000226212	SCV000265790	likely pathogenic	Congenital myopathy 4B, autosomal recessive	2015-12-01	criteria provided, single submitter	research
GeneDx	RCV000128699	SCV000589663	pathogenic	not provided	2017-04-27	criteria provided, single submitter	clinical testing	The R168G variant in the TPM3 gene has been reported previously in an individual with congenital fiber type disproportion (Clarke et al., 2008). Functional studies of the R168G variant indicate a decreased affinity for actin and reduced calcium-induced ATPase activation (Robaszkiewicz et al., 2012; Yuen et al., 2015). Different missense variants in the same codon (R168C, R168H) have been reported in association with TPM3-related disorders (Clarke et al., 2008; Waddell et al., 2010; Marttila et al., 2014). The R168G variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R168G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001382225	SCV001580897	pathogenic	Congenital myopathy 4B, autosomal recessive; Congenital myopathy with fiber type disproportion	2023-04-12	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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, 18300303, 20554445, 24095155, 24692096). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects TPM3 function (PMID: 22749829). 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. ClinVar contains an entry for this variant (Variation ID: 12453). This missense change has been observed in individuals with clinical features of autosomal dominant congenital myopathy and/or congenital fiber type disproportion (PMID: 18300303, 27854218; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 168 of the TPM3 protein (p.Arg168Gly).
Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire	RCV004585998	SCV005038511	pathogenic	TPM3-related core myopathy	2024-03-01	criteria provided, single submitter	research	PS3+PM1+PM2+PM5+PM6+PP2+PP3
OMIM	RCV003151725	SCV000033515	pathogenic	Congenital myopathy 4A, autosomal dominant	2008-03-01	no assertion criteria provided	literature only
GeneReviews	RCV000013268	SCV000058559	not provided	Congenital myopathy with fiber type disproportion		no assertion provided	literature only
TPM3 homepage - Leiden Muscular Dystrophy pages	RCV000128699	SCV000172339	not provided	not provided		no assertion provided	not provided