Submissions for variant NM_000070.3(CAPN3):c.593A>G (p.Asn198Ser)

gnomAD frequency: 0.00006  dbSNP: rs371166254

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000480853	SCV000568284	uncertain significance	not provided	2016-06-23	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the CAPN3 gene. The c.593 A>G variant has been reported previously in two individuals with a clinical diagnosis of limb-girdle muscular dystrophy who had decreased CAPN3 protein on Western blot; both of these individuals had a second CAPN3 variant identified (Krahn et al., 2006; Burke et al., 2010). The c.593 A>G variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. Several in-silico splice prediction models predict that c.593 A>G creates a cryptic donor site which may supplant the natural donor site and lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. If c.593 A>G does not affect splicing, it will result in the N198S missense change. The N198S variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species, and missense variants in nearby residues (S194C, R197H, R197L, E199Q) have been reported in the Human Gene Mutation Database in association with limb-girdle muscular dystrophy (Stenson et al., 2014), supporting the functional importance of this region of the protein. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000528940	SCV000645506	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2A	2024-04-24	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 198 of the CAPN3 protein (p.Asn198Ser). This variant is present in population databases (rs371166254, gnomAD 0.005%). This missense change has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy (PMID: 16650086, 20580976). ClinVar contains an entry for this variant (Variation ID: 420001). 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%. Studies have shown that this missense change alters CAPN3 gene expression (PMID: 20580976). Studies have shown that this missense change does not affect mRNA splicing (PMID: 32668095). 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.
Counsyl	RCV000528940	SCV000800198	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2A	2018-05-24	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000480853	SCV003828957	uncertain significance	not provided	2021-11-29	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003476161	SCV004211557	likely pathogenic	Muscular dystrophy, limb-girdle, autosomal dominant 4	2024-03-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004767291	SCV005381227	uncertain significance	not specified	2024-08-07	criteria provided, single submitter	clinical testing	Variant summary: CAPN3 c.593A>G (p.Asn198Ser) results in a 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 1.2e-05 in 251468 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.593A>G has been reported in the literature in a compound heterozygous individual affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (Krahn_2006) and in a heterozygous individual with clinical features of Limb-Girdle Muscular Dystrophy who also carries a missense variant in the COL6A3 gene with unknown significance (Lin_2023). 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. The following publications have been ascertained in the context of this evaluation (PMID: 16650086, 37974208). ClinVar contains an entry for this variant (Variation ID: 420001). Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc.	RCV000528940	SCV001461312	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2A	2020-09-16	no assertion criteria provided	clinical testing