Submissions for variant NM_000070.3(CAPN3):c.1303G>A (p.Glu435Lys)

gnomAD frequency: 0.00008  dbSNP: rs149914792

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000440492	SCV000333467	pathogenic	not provided	2018-08-29	criteria provided, single submitter	clinical testing
GeneDx	RCV000440492	SCV000520879	likely pathogenic	not provided	2025-02-19	criteria provided, single submitter	clinical testing	Reported in the heterozygous state without a second identifiable CAPN3 variant in an individual with late onset limb girdle muscular dystrophy who had complete calpain-3 deficiency on Western blot (PMID: 15221789); Not observed at significant frequency in large population cohorts (gnomAD); 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: 19226146, 16141003, 31589614, 32528171, 18854869, 11371436, 26363099, 34149409, Aksu2020[casereport], 20635405, 23553538, 35157181, 33931068, 38812636, 15221789)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000820741	SCV000961467	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2025-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 435 of the CAPN3 protein (p.Glu435Lys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (PMID: 18854869, 20635405, 23553538, 33931068). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 282173). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt CAPN3 protein function with a negative 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.
Athena Diagnostics	RCV000440492	SCV001143415	likely pathogenic	not provided	2024-11-27	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity. (http://gnomad.broadinstitute.org) Assessment of experimental evidence regarding the effect of this variant on protein function is inconclusive. Experiments performed in the paralagous protein, calpain-2 of rat, suggest this variant increases autocatalytic activity, however, it is unclear if this would also be true in calpain-3. 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.
Genome-Nilou Lab	RCV000820741	SCV001653420	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2021-05-18	criteria provided, single submitter	clinical testing
DASA	RCV001775111	SCV002011892	pathogenic	Limb-girdle muscular dystrophy	2021-09-02	criteria provided, single submitter	clinical testing	The c.1303G>A;p.(Glu435Lys) variant has been published as a pathogenic variant in individuals affected with limb-girdle muscular dystrophy (PMID 15221789; 16141003; 18854869; 20635405; GeneOne, DASA) and ClinVar contains an entry for this variant (Variation ID: 13263) - PS4_moderate; variant is located in a mutational hot spot and/or critical and well-established functional domain (Calpain_III) - PM1; this variant is present in population databases (rs149914792 - gnomAD 0.0092% frequency; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting; variant detected in trans with a pathogenic variant (PMID 18854869; 20635405) - PM3_strong; this variant has been observed to segregate in a family (PMID: 20635405) - PP1; in silico analysis predicts this variant is probably damaging to the protein structure/function - PP3; In summary, the currently available evidence indicates that the variant is pathogenic.
Revvity Omics, Revvity	RCV000440492	SCV002018073	pathogenic	not provided	2022-04-26	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002480004	SCV002804382	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A; Muscular dystrophy, limb-girdle, autosomal dominant 4	2024-05-07	criteria provided, single submitter	clinical testing
Eurofins-Biomnis	RCV000820741	SCV003935051	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2022-10-20	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000440492	SCV004041923	likely pathogenic	not provided	2023-09-01	criteria provided, single submitter	clinical testing	CAPN3: PM1, PM3, PM2:Supporting, PP3
Baylor Genetics	RCV003475891	SCV004211511	likely pathogenic	Muscular dystrophy, limb-girdle, autosomal dominant 4	2024-03-20	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000820741	SCV005052052	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2024-02-01	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004689699	SCV005186046	pathogenic	Autosomal recessive limb-girdle muscular dystrophy	2024-05-02	criteria provided, single submitter	clinical testing	Variant summary: CAPN3 c.1303G>A (p.Glu435Lys) results in a conservative amino acid change located in the Peptidase C2, calpain, large subunit, domain III (IPR022682) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-05 in 250332 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CAPN3 causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (8.4e-05 vs 0.0032), allowing no conclusion about variant significance. c.1303G>A has been reported in the literature in homozygous and compound heterozygous individuals affected with Limb-Girdle Muscular Dystrophy, hyperCkemia, or with clinical symptoms of a neuromuscular disorder or in heterozygous individuals without reported second variant (e.g. Ozyilmaz_2022, Fanin_2009, Saenz_2005, Piluso_2004, Topf_2020, Quick_2021). These data indicate that the variant is likely to be associated with disease. Several publications provide functional evidence suggesting the variant causes significant deficits of calpain-3 quantity and loss of autolytic activity in vitro (e.g. Fanin_2009) or accelerates autolytic degradation, lowering overall enzyme activity (e.g. Granham_2009). The following publications have been ascertained in the context of this evaluation (PMID: 18854869, 19226146, 35157181, 16141003, 33931068, 15689361, 32528171). ClinVar contains an entry for this variant (Variation ID: 282173). Based on the evidence outlined above, the variant was classified as pathogenic.
Natera, Inc.	RCV000820741	SCV002085503	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2020-01-16	no assertion criteria provided	clinical testing