ClinVar Miner

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

dbSNP: rs121964852
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000537032 SCV000635068 pathogenic Congenital myopathy 4B, autosomal recessive; Congenital myopathy with fiber type disproportion 2023-04-12 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 168 of the TPM3 protein (p.Arg168His). This variant is not present in population databases (gnomAD no frequency). 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: 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: 21357678, 22749829, 22798622, 23886664). 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 not expected to disrupt TPM3 protein function. ClinVar contains an entry for this variant (Variation ID: 12450). This variant is also known as p.Arg167His. This missense change has been observed in individual(s) with autosomal dominant nemaline myopathy, cap myopathy, congenital myopathy, and congenital fiber type disproportion (PMID: 12467750, 17376686, 19553118, 21357678, 24507666, 24692096). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals.
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.
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000013263 SCV001251922 pathogenic Congenital myopathy 4B, autosomal recessive 2020-05-03 criteria provided, single submitter clinical testing
Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli RCV001420249 SCV001622669 pathogenic See cases 2021-04-26 criteria provided, single submitter clinical testing PP5_very strong;PS3_strong;PM2_supporting;PM5_moderate;PP2_supporting;PP3_supporting
GeneDx RCV000128701 SCV001818927 pathogenic not provided 2021-11-01 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 12467750, 22749829, 23886664, 22798622, 24692096, 17376686, 26307083, 19553118, 18300303, 19953533, 20951040, 32140910, 33333461, 31270709)
Mayo Clinic Laboratories, Mayo Clinic RCV000128701 SCV002520039 pathogenic not provided 2021-07-22 criteria provided, single submitter clinical testing PP1, PP3, PM2, PM6, PS3, PS4_moderate
CeGaT Center for Human Genetics Tuebingen RCV000128701 SCV003916500 pathogenic not provided 2023-03-01 criteria provided, single submitter clinical testing TPM3: PM1, PM2, PM5, PS4:Moderate, PP3, PS3:Supporting
OMIM RCV000054415 SCV000033510 pathogenic Congenital myopathy 4A, autosomal dominant 2009-10-01 no assertion criteria provided literature only
GeneReviews RCV000013263 SCV000058561 not provided Congenital myopathy 4B, autosomal recessive no assertion provided literature only
TPM3 homepage - Leiden Muscular Dystrophy pages RCV000128701 SCV000172341 not provided not provided no assertion provided not provided

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