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

dbSNP: rs121964852

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	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	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