Submissions for variant NM_000070.3(CAPN3):c.397G>A (p.Ala133Thr)

dbSNP: rs946415346

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001068857	SCV001233990	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2023-09-08	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 862181). 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 CAPN3 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 133 of the CAPN3 protein (p.Ala133Thr). This missense change has been observed in individual(s) with limb-girdle muscular dystrophy (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003479277	SCV004223699	uncertain significance	not specified	2023-11-13	criteria provided, single submitter	clinical testing	Variant summary: CAPN3 c.397G>A (p.Ala133Thr) results in a non-conservative amino acid change located in the Peptidase C2, calpain, catalytic domain (IPR001300) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251410 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.397G>A in individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as likely pathogenic, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Neurogenomics Lab, Neuroscience Institute, University Of Cape Town	RCV001068857	SCV004698003	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2024-05-22	criteria provided, single submitter	research	PM2_Supporting: the highest population allele frequency in gnomAD v4.0 is 0.00001656 (0.002%; 1/60388 alleles in Remaining population) and there are no homozygous observations. PP3_Moderare: REVEL score is 0.907. PM1 Not Met: pathogenic variants are distributed throughout the protein. PM3 Met: 1.5 points awarded for 2 observations of variant with another pathogenic CAPN3 variant, one with phase unknown (PMID 37526466) and one confirmed in trans (ClinVar SCV001233990.5). PM5 Met: NM_000070.3(CAPN3):c.398C>T (p.Ala133Val) classified as likely pathogenic (PM2_Supporting, PP3_Strong, PM3 Met). Sequencing funded by the International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD): https://www.ucl.ac.uk/genomic-medicine-neuromuscular-diseases/.
Natera, Inc.	RCV001068857	SCV002094443	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2A	2021-02-05	no assertion criteria provided	clinical testing