Submissions for variant NM_000070.3(CAPN3):c.304C>T (p.Pro102Ser)

dbSNP: rs2141102957

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001909388	SCV002187254	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2A	2023-05-26	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 102 of the CAPN3 protein (p.Pro102Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (PMID: 16141003, 35169782). ClinVar contains an entry for this variant (Variation ID: 1407933). 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 expected to disrupt CAPN3 protein function. 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.
Neuberg Centre For Genomic Medicine, NCGM	RCV001909388	SCV005373645	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2A	2023-05-20	criteria provided, single submitter	clinical testing	The missense variant c.304C>T(p.Pro102Ser) in the CAPN3 gene has been reported previously in an individual affected with limb girdle muscular dystrophy (Piluso et al., 2005). The variant is absent in the gnomAD Exomes. It is submitted to ClinVar as Uncertain Significance. However, study on multiple affected individuals and functional impact of the variant is not available. The amino acid Proline at position 102 is changed to a Serine changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (Polyphen - Damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The amino acid change p.Pro102Ser in CAPN3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. However further literature and functional evidence will be required to prove the pathogenicity. For these reasons, this variant has been classified as Uncertain Significance.