Submissions for variant NM_152263.4(TPM3):c.502C>T (p.Arg168Cys)

dbSNP: rs121964854

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000128700	SCV000329559	pathogenic	not provided	2022-12-28	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a decreased affinity for actin and reduced calcium-induced ATPase activation (Robaszkiewicz et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24692096, 24642510, 24456932, 20301436, 12467750, 32675003, 22749829, 19181092, 26307083, 18300303, 20554445, 24095155, 24507666, 19487656, 24239060, 20179953, 22172422, 23584160, 27363342, 29669168, 23886664, 22798622, 21357678, 19953533, 19553118, 17376686, 12601110, 12196661, 12163190, 10619715, 33646172, 33064836, 33652732, 33333461)
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000128700	SCV000609700	pathogenic	not provided	2017-04-11	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000128700	SCV000703292	pathogenic	not provided	2016-11-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000624745	SCV000741605	pathogenic	Inborn genetic diseases	2016-06-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000637291	SCV000758739	pathogenic	Congenital myopathy 4B, autosomal recessive; Congenital myopathy with fiber type disproportion	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 168 of the TPM3 protein (p.Arg168Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with congenital myopathy, cap myopathy, nemaline myopathy, and congenital fiber type disproportion (PMID: 18300303, 19487656, 19953533, 20554445, 24095155, 24507666, 24642510, 24692096, 26307083, 27363342). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 12454). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects TPM3 function (PMID: 22749829, 26307083). 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, 19553118, 21357678, 22749829, 22798622, 23886664, 24507666, 24692096). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000128700	SCV002022397	pathogenic	not provided	2019-06-21	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000128700	SCV002585155	pathogenic	not provided	2022-09-01	criteria provided, single submitter	clinical testing	TPM3: PM2, PM5, PM6, PS4:Moderate, PP3, PP4, PS3:Supporting
Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire	RCV004585999	SCV005038510	pathogenic	Nemaline myopathy	2024-03-01	criteria provided, single submitter	research	PS3+PM1+PM2+PM5+PM6+PP2+PP3
Suma Genomics	RCV000054416	SCV005341000	pathogenic	Congenital myopathy 4A, autosomal dominant		criteria provided, single submitter	clinical testing	A missense variant c.502C>T, p.(Arg168Cys) is observed in exon 5 of TPM3 in heterozygous state. This variant is not observed in the gnomAD database. This variant was reported earlier in the ClinVar database as pathogenic (ClinVar id. 12454). ACMG criteria: PS2, PS3, PM1, PM2_Supporting, PM6 and PP3
OMIM	RCV000054416	SCV000033516	pathogenic	Congenital myopathy 4A, autosomal dominant	2013-12-01	no assertion criteria provided	literature only
GeneReviews	RCV000013269	SCV000058560	not provided	Congenital myopathy with fiber type disproportion		no assertion provided	literature only
TPM3 homepage - Leiden Muscular Dystrophy pages	RCV000128700	SCV000172340	not provided	not provided		no assertion provided	not provided