Submissions for variant NM_000070.3(CAPN3):c.1984G>T (p.Ala662Ser)

gnomAD frequency: 0.00011  dbSNP: rs187054121

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000536114	SCV000645484	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2A	2024-10-28	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 662 of the CAPN3 protein (p.Ala662Ser). This variant is present in population databases (rs187054121, gnomAD 0.2%). This missense change has been observed in individual(s) with limb-girdle muscular dystrophy (PMID: 1691480, 16141003, 18854869). ClinVar contains an entry for this variant (Variation ID: 468646). 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%. 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.
Eurofins Ntd Llc (ga)	RCV000596889	SCV000704297	uncertain significance	not provided	2018-06-08	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000536114	SCV001275946	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2A	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Pars Genome Lab	RCV000536114	SCV001736799	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2A	2021-05-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000596889	SCV001811254	uncertain significance	not provided	2019-07-19	criteria provided, single submitter	clinical testing	Reported previously in a patient with late-onset limb-girdle muscular dystrophy who did not have a second identifiable pathogenic CAPN3 variant (Fanin et al., 2007); Reported previously in a patient with limb-girdle muscular dystrophy who harbored another CAPN3 missense variant and results of a functional test showed this patient had loss of calpain-3 of autolytic activity (Fanin et al., 2009); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 18854869, 1691480, 25898921, 16971480, 16141003, 25525159)
Fulgent Genetics, Fulgent Genetics	RCV002491062	SCV002777463	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2A; Muscular dystrophy, limb-girdle, autosomal dominant 4	2021-09-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000596889	SCV003828977	uncertain significance	not provided	2024-01-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488681	SCV004240886	uncertain significance	not specified	2023-12-12	criteria provided, single submitter	clinical testing	Variant summary: CAPN3 c.1984G>T (p.Ala662Ser) results in a conservative amino acid change located in the penta-EF-hand (PEF) domain (IPR029531) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00023 in 1,607,152 control chromosomes, predominantly at a frequency of 0.0019 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than the estimated maximum expected for a pathogenic variant in CAPN3 causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (0.0032), allowing no conclusion about variant significance. The variant, c.1984G>T, has been reported in the literature in heterozygous state (i.e. without identifying a second variant) in individuals affected with Limb-Girdle Muscular Dystrophy (e.g. Piluso_2005, Fanin_2007, Nallamilli_2018); where muscle biopsy specimen from one of these patients demonstrated loss of calpain-3 autolytic activity (Fanin_2007). These reports do not provide unequivocal conclusions about association of the variant with Limb-Girdle Muscular Dystrophy, Autosomal Recessive. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 16141003, 16971480, 30564623). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc.	RCV000536114	SCV001456367	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2A	2020-09-16	no assertion criteria provided	clinical testing