ClinVar Miner

Submissions for variant NM_152263.4(TPM3):c.502C>T (p.Arg168Cys) (rs121964854)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000128700 SCV000329559 pathogenic not provided 2016-07-19 criteria provided, single submitter clinical testing The R168C pathogenic variant in the TPM3 gene has been reported previously multiple times in the heterozygous state in association with congenital fiber-type disproportion (CFTD), nemaline myopathy type 1 (NM1), and cap myopathy (Clarke et al., 2008; Waddell et al., 2010; Marttila et al., 2014). R168C has been reported to cause histological changes characteristic of CFTD, NM, and cap myopathy (Waddell et al., 2010; Marttila et al., 2014). Functional studies of the R168C pathogenic variant indicate a decreased affinity for actin and reduced calcium-induced ATPase activation (Robaszkiewicz et al., 2012). Different missense variants at the same location (R168H and R168G) have also been reported to cause autosomal dominant NM1 or CFTD (Clarke et al., 2008; Marttila et al., 2014), supporting the functional importance of this residue of the protein. The R168C pathogenic variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In addition, the R168C 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. Therefore, we interpret R168C as a pathogenic variant.
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
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics 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 Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Invitae RCV000637291 SCV000758739 pathogenic Nemaline myopathy 1; Congenital myopathy with fiber type disproportion 2018-06-12 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 168 of the TPM3 protein (p.Arg168Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals and families affected with congenital myopathy, cap myopathy, nemaline myopathy, and congenital fiber type disproportion (PMID: 24095155, 20554445, 18300303, 26307083, 27363342, 24642510, 24692096, 24507666, 19487656). This variant has also been found to be de novo in affected individuals (PMID: 20554445, 24095155, 18300303, 19953533). ClinVar contains an entry for this variant (Variation ID: 12454). Experimental studies have shown that this missense change alters protein function in vitro (PMID: 22749829, 26307083). A different missense substitution at this codon (p.Arg168His) has been determined to be pathogenic (PMID: 17376686, 24507666, 19553118, 12467750, 21357678, 24692096, 22749829, 23886664, 22798622). This suggests that the arginine residue is critical for TPM3 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000013269 SCV000033516 pathogenic Congenital myopathy with fiber type disproportion 2013-12-01 no assertion criteria provided literature only
GeneReviews RCV000013269 SCV000058560 pathologic Congenital myopathy with fiber type disproportion 2013-04-11 no assertion criteria provided curation Converted during submission to Pathogenic.
OMIM RCV000054416 SCV000082893 pathogenic Cap myopathy 1 2013-12-01 no assertion criteria provided literature only
TPM3 homepage - Leiden Muscular Dystrophy pages RCV000128700 SCV000172340 not provided not provided no assertion provided not provided

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