Submissions for variant NM_000070.3(CAPN3):c.721A>G (p.Ile241Val)

gnomAD frequency: 0.00015  dbSNP: rs141948992

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000726613	SCV000345827	uncertain significance	not provided	2016-09-07	criteria provided, single submitter	clinical testing
GeneDx	RCV000726613	SCV000619565	uncertain significance	not provided	2018-11-13	criteria provided, single submitter	clinical testing	The c.721 A>G variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.721 A>G variant is observed in 19/66,740 (0.03%) alleles from individuals of European background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Multiple in-silico splice prediction models predict that c.721 A>G creates a cryptic splice donor site which may supplant the natural splice donor site and lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change on splicing is unknown. If c.721 A>G does not alter splicing, it will result in the I241V missense change. The I241V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Isoleucine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000806753	SCV000946769	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2A	2025-01-05	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 241 of the CAPN3 protein (p.Ile241Val). This variant is present in population databases (rs141948992, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with CAPN3-related conditions. ClinVar contains an entry for this variant (Variation ID: 291126). 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000726613	SCV001716212	uncertain significance	not provided	2020-04-06	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000726613	SCV003828978	uncertain significance	not provided	2022-06-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004021323	SCV004919363	uncertain significance	Inborn genetic diseases	2023-09-20	criteria provided, single submitter	clinical testing	The c.721A>G (p.I241V) alteration is located in exon 5 (coding exon 5) of the CAPN3 gene. This alteration results from a A to G substitution at nucleotide position 721, causing the isoleucine (I) at amino acid position 241 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Natera, Inc.	RCV000806753	SCV001456719	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2A	2020-01-24	no assertion criteria provided	clinical testing