Submissions for variant NM_000070.3(CAPN3):c.1336G>A (p.Gly446Ser)

dbSNP: rs886042857

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000397376	SCV000336981	uncertain significance	not provided	2015-11-03	criteria provided, single submitter	clinical testing
Invitae	RCV000707427	SCV000836525	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2A	2022-09-13	criteria provided, single submitter	clinical testing	Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. 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. ClinVar contains an entry for this variant (Variation ID: 284385). This missense change has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy (PMID: 22443334, 30919934). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 446 of the CAPN3 protein (p.Gly446Ser).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282103	SCV002571086	uncertain significance	not specified	2022-07-14	criteria provided, single submitter	clinical testing	Variant summary: CAPN3 c.1336G>A (p.Gly446Ser) results in a non-conservative amino acid change located in the Peptidase C2, calpain, large subunit, domain III (IPR022682) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 238580 control chromosomes (gnomAD). c.1336G>A has been reported in the literature in individuals affected with Limb-Girdle Muscular Dystrophy, including one homozygote (Hauerslev_2012) and one compound heterozygote (Ten Dam_2019). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters have assessed the variant since 2014: both classified the variant as of uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.