Submissions for variant NM_000070.3(CAPN3):c.2305C>T (p.Arg769Trp)

dbSNP: rs868791726

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000711016	SCV000333873	likely pathogenic	not provided	2017-04-12	criteria provided, single submitter	clinical testing
Invitae	RCV000295812	SCV000645494	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2023-11-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 769 of the CAPN3 protein (p.Arg769Trp). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy (PMID: 20517216, 26060040, 27066551, 28403181). ClinVar contains an entry for this variant (Variation ID: 282411). 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 with a positive predictive value of 80%. This variant disrupts the p.Arg769 amino acid residue in CAPN3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7720071, 7762565, 7795603, 12461690, 14645990). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics Inc	RCV000711016	SCV000841334	likely pathogenic	not provided	2020-02-25	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. One other pathogenic or likely pathogenic variant affects the same amino acid. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic.
Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli	RCV001420333	SCV001622753	pathogenic	See cases	2021-04-26	criteria provided, single submitter	clinical testing	PP5_strong;PM1_moderate;PM2_supporting;PM3_moderate;PM5_moderate;PP3_supporting;BP1_supporting
Revvity Omics, Revvity	RCV000711016	SCV002025065	likely pathogenic	not provided	2023-06-02	criteria provided, single submitter	clinical testing
Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	RCV000295812	SCV002574848	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2022-09-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323488	SCV004029394	pathogenic	Autosomal recessive limb-girdle muscular dystrophy	2023-07-26	criteria provided, single submitter	clinical testing	Variant summary: CAPN3 c.2305C>T (p.Arg769Trp) results in a non-conservative amino acid change located in the EF hand domain (IPR002048) of the encoded protein sequence. Five 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 251388 control chromosomes (gnomAD). c.2305C>T has been reported in the literature in individuals affected with Limb-Girdle Muscular Dystrophy (example: Nallamilli_2018, Yu_2017, Tian_2015). Other variant affecting the same codon has been classified pathogenic in ClinVar (p.Arg769Gln CV ID 17613) The following publications have been ascertained in the context of this evaluation (PMID: 30564623, 27066551, 28403181). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV003475893	SCV004211562	pathogenic	Muscular dystrophy, limb-girdle, autosomal dominant 4	2023-09-13	criteria provided, single submitter	clinical testing
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000295812	SCV004227899	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A		criteria provided, single submitter	clinical testing
Counsyl	RCV000295812	SCV000791434	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2017-05-16	no assertion criteria provided	clinical testing