ClinVar Miner

Submissions for variant NM_152263.4(TPM3):c.503G>A (p.Arg168His) (rs121964852)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000537032 SCV000635068 pathogenic Nemaline myopathy 1; Congenital myopathy with fiber type disproportion 2017-05-02 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 168 of the TPM3 protein (p.Arg168His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals and families affected with autosomal dominant nemaline myopathy, cap myopathy, congenital myopathy, and congenital fiber type disproportion (PMID: 17376686, 24507666, 19553118, 12467750, 21357678, 24692096). This variant has been shown to arise de novo in an individual affected with nemaline myopathy (PMID: 12467750). In addition, this variant has been shown to segregate with disease in a family with nemaline myopathy (PMID: 17376686). This variant is also known as p.Arg167His in the literature. ClinVar contains an entry for this variant (Variation ID: 12450). Experimental studies have shown that this missense change significantly alters protein function (PMID: 22749829, 21357678, 23886664, 22798622). A different missense substitution at this codon (p.Arg168Cys) has been determined to be pathogenic (PMID: 24692096, 24095155). 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.
Athena Diagnostics Inc RCV000128701 SCV001146217 pathogenic not provided 2018-08-29 criteria provided, single submitter clinical testing Not found in the total gnomAD dataset, and the data is high quality (0/277230 chr). Found in at least one symptomatic patient. Conflicting predictions of the effect on the protein. Two other pathogenic or likely pathogenic variants affect the same amino acid. Damaging to protein function(s) relevant to disease mechanism. Moderate co-segregation with disease, and data include both affected and unaffected members from multiple families. 3 de novo cases without parental identity confirmed. 1 de novo case with parental identity confirmed.
OMIM RCV000013263 SCV000033510 pathogenic Nemaline myopathy 1 2009-10-01 no assertion criteria provided literature only
OMIM RCV000013264 SCV000033511 pathogenic Congenital myopathy with fiber type disproportion 2009-10-01 no assertion criteria provided literature only
GeneReviews RCV000013263 SCV000058561 pathologic Nemaline myopathy 1 2013-04-11 no assertion criteria provided curation Converted during submission to Pathogenic.
OMIM RCV000054415 SCV000082892 pathogenic Cap myopathy 1 2009-10-01 no assertion criteria provided literature only
TPM3 homepage - Leiden Muscular Dystrophy pages RCV000128701 SCV000172341 not provided not provided no assertion provided not provided

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.