Submissions for variant NM_000070.3(CAPN3):c.1250C>T (p.Thr417Met)

gnomAD frequency: 0.00006  dbSNP: rs200646556

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000724905	SCV000332311	pathogenic	not provided	2017-04-12	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000340100	SCV000823944	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 417 of the CAPN3 protein (p.Thr417Met). This variant is present in population databases (rs200646556, gnomAD 0.008%). This missense change has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy (PMID: 16650086, 20517216, 25079074, 25135358). ClinVar contains an entry for this variant (Variation ID: 281505). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CAPN3 function (PMID: 19226146). For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000340100	SCV001164477	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2018-12-03	criteria provided, single submitter	research	The heterozygous p.Thr417Met variant in CAPN3 was identified by our study in the compound heterozygous state, with a pathogenic variant, in one individual with limb-girdle muscular dystrophy (LGMD) Trio exome analysis showed this variant to be de novo. The p.Thr417Met variant in CAPN3 has been reported in 4 individuals (including 1 French, 1 European Canadian individual) with LGMD (PMID: 25135358, 25079074,16650086), and has been identified in 0.008324% (2/24026) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs200646556). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Animal models in rats have shown that this variant impacts calcium binding for the protein and causes LGMD (PMID: 19226146). The presence of this variant in combination with 2 reported pathogenic variants, p.Thr184Argfs and p.Glu622Argfs, and in 2 individuals with LGMD increases the likelihood that the p.Thr417Met variant is pathogenic (Variation ID: 17621, 290296). This variant has also been reported pathogenic in ClinVar (Variation ID: 281505). In summary, this variant meets criteria to be classified as pathogenic for LGMD in an autosomal recessive manner based on the predicted impact of the variant, functional evidence, and multiple occurrences with pathogenic CAPN3 variants in individuals with LGMD. ACMG/AMP Criteria applied: PM2, PS2, PP3, PM3_Strong, PS3_Moderate (Richards 2015).
CeGaT Center for Human Genetics Tuebingen	RCV000724905	SCV001247166	pathogenic	not provided	2024-02-01	criteria provided, single submitter	clinical testing	CAPN3: PM3:Very Strong, PM2, PP3, PS3:Supporting
Athena Diagnostics	RCV000724905	SCV001476310	pathogenic	not provided	2020-06-02	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity. Predicted to have a damaging effect on the protein. This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001814141	SCV001755319	pathogenic	Abnormality of the musculature	2021-07-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000724905	SCV001871047	likely pathogenic	not provided	2023-06-22	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25135358, 19226146, 15689361, 19556129, 25214167, 25079074, 16650086, 32703463, 29792937, 31788660, 32528171, 32668095, Koken_2022_Abstract, 34440373)
Revvity Omics, Revvity	RCV000724905	SCV002025058	likely pathogenic	not provided	2020-10-12	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000724905	SCV002520051	pathogenic	not provided	2021-04-30	criteria provided, single submitter	clinical testing	PS3, PM2, PS4_moderate, PP3, PP4
Fulgent Genetics, Fulgent Genetics	RCV002502096	SCV002808724	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A; Muscular dystrophy, limb-girdle, autosomal dominant 4	2022-03-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002509343	SCV002819385	pathogenic	Autosomal recessive limb-girdle muscular dystrophy	2022-12-02	criteria provided, single submitter	clinical testing	Variant summary: CAPN3 c.1250C>T (p.Thr417Met) 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 allele was found at a frequency of 5.2e-05 in 251420 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CAPN3 causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (5.2e-05 vs 0.0032), allowing no conclusion about variant significance. c.1250C>T has been reported in the literature as biallelic genotypes in multiple individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (example, PMID: 15689361, 18258189, 25135358, 27447704, 34440373, 25079074, 16650086). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV003475890	SCV004211535	pathogenic	Muscular dystrophy, limb-girdle, autosomal dominant 4	2024-03-21	criteria provided, single submitter	clinical testing
Counsyl	RCV000340100	SCV000790013	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2017-03-01	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000340100	SCV001454338	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2020-09-16	no assertion criteria provided	clinical testing