Submissions for variant NM_000070.3(CAPN3):c.338T>C (p.Ile113Thr)

gnomAD frequency: 0.00015  dbSNP: rs747026964

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000440617	SCV000335003	uncertain significance	not provided	2018-07-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000440617	SCV000533388	likely pathogenic	not provided	2023-06-08	criteria provided, single submitter	clinical testing	Identified in the presence of a second CAPN3 variant, in a patient with early onset pelvifemoral LGMD2A, however CAPN3 enzyme deficiency was not detected (Nilsson et al., 2014).; Identified heterozygous by NGS panel testing in three patients with LGMD2A, however no second variant was identified (Nallamilli et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25079074, 30564623)
Counsyl	RCV000675143	SCV000800733	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2A	2017-09-15	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000675143	SCV000914667	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2A	2018-01-29	criteria provided, single submitter	clinical testing	The CAPN3 c.338T>C (p.Ile113Thr) variant has been reported in a compound heterozygous state with a second missense variant in one patient with limb-girdle muscular dystrophy type 2A (LGMD2A) (Nilsson et al. 2014). The p.Ile113Thr is reported at a frequency of 0.000213 in the European (non-Finnish) population from the Genome Aggregation Database. The evidence for this variant is limited. The p.Ile113Thr variant is therefore considered to be of unknown clinical significance but suspicious for pathogenicity for calpainopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Baylor Genetics	RCV000675143	SCV001529404	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282100	SCV002572258	uncertain significance	not specified	2022-08-23	criteria provided, single submitter	clinical testing	Variant summary: CAPN3 c.338T>C (p.Ile113Thr) results in a non-conservative amino acid change located in the Peptidase C2, calpain, catalytic domain (IPR001300) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.1e-05 in 251430 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CAPN3 causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (9.1e-05 vs 0.0032), allowing no conclusion about variant significance. c.338T>C has been reported in the literature as a compound heterozygous genotype in at-least one individual affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (example, Nilsson_2014) and as a VUS with a non-informative genotype (second allele not specified) in at-least three individuals within a cohort sequenced for Limb-girdle muscular dystrophies (LGMDs) at a reference laboratory (example, Nallamilli_2018). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Likely pathogenic, n=1; VUS, n=4). Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000675143	SCV002943387	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2A	2022-11-02	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 113 of the CAPN3 protein (p.Ile113Thr). This variant is present in population databases (rs747026964, gnomAD 0.02%). This missense change has been observed in individual(s) with limb-girdle muscular dystrophy (PMID: 25079074, 30564623). ClinVar contains an entry for this variant (Variation ID: 283107). 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 CAPN3 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Revvity Omics, Revvity	RCV000440617	SCV003828963	uncertain significance	not provided	2022-07-21	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003475901	SCV004211503	likely pathogenic	Muscular dystrophy, limb-girdle, autosomal dominant 4	2024-03-28	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000440617	SCV004227365	uncertain significance	not provided	2023-06-22	criteria provided, single submitter	clinical testing	PM3
PreventionGenetics, part of Exact Sciences	RCV004732820	SCV005362603	uncertain significance	CAPN3-related disorder	2024-05-29	no assertion criteria provided	clinical testing	The CAPN3 c.338T>C variant is predicted to result in the amino acid substitution p.Ile113Thr. This variant has been reported in multiple individuals with limb-girdle muscular dystrophy; however, it is not clear if a second CAPN3 variant was identified in some of these patients (Table S7, Nallamilli et al. 2018. PubMed ID: 30564623; Table 1, Nilsson et al. 2014. PubMed ID: 25079074). This variant is reported in 0.022% of alleles in individuals of European (non-Finnish) descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.