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

gnomAD frequency: 0.00008  dbSNP: rs149914792

Total submissions: 12

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	2023-06-30	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 (Fanin et al., 2004).; 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, 15221789)
Invitae	RCV000820741	SCV000961467	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2024-01-25	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). 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). 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 with a negative predictive value of 80%. Experimental studies have shown that this missense change affects CAPN3 function (PMID: 19226146). 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.
Athena Diagnostics Inc	RCV000440492	SCV001143415	likely pathogenic	not provided	2019-05-03	criteria provided, single submitter	clinical testing	The best available variant frequency is uninformative because it is below the disease allele frequency. Found in at least one symptomatic patient. Conflicting predictions of the effect on the protein. Occurs in three or more cases with a recessive pathogenic variant in the same gene. Results on protein functions were inconclusive. Inconclusive segregation with disease.
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	2022-05-18	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	2023-10-24	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000820741	SCV002085503	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2020-01-16	no assertion criteria provided	clinical testing