Submissions for variant NM_000070.3(CAPN3):c.1621C>T (p.Arg541Trp)

gnomAD frequency: 0.00001  dbSNP: rs142004418

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000726807	SCV000703198	pathogenic	not provided	2018-08-31	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000762951	SCV000893375	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A; Muscular dystrophy, limb-girdle, autosomal dominant 4	2018-10-31	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000595213	SCV001164528	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2A	2018-12-03	criteria provided, single submitter	research	The homozygous p.Arg541Trp variant in CAPN3 was identified by our study in three unrelated individuals with limb-girdle muscular dystrophy (LGMD). The presence of this variant in the homozygous state and in individuals with LGMD increases the likelihood that the p.Arg541Trp variant is pathogenic. This variant has been identified in 0.003656% (9/246196) of chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs142004418). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Arg541Trp variant is uncertain. ACMG/AMP Criteria applied: PM2, PM3, PP3 (Richards 2015).
Invitae	RCV000595213	SCV001220736	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2024-01-04	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 541 of the CAPN3 protein (p.Arg541Trp). This variant is present in population databases (rs142004418, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (PMID: 16100770, 18854869, 19556129). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 498267). 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%. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000726807	SCV001247173	pathogenic	not provided	2023-07-01	criteria provided, single submitter	clinical testing	CAPN3: PM3:Very Strong, PM2, PM5, PP3
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000726807	SCV001446547	likely pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002298702	SCV002599071	pathogenic	Autosomal recessive limb-girdle muscular dystrophy	2022-09-02	criteria provided, single submitter	clinical testing	Variant summary: CAPN3 c.1621C>T (p.Arg541Trp) results in a non-conservative amino acid change located in the Peptidase C2, calpain, domain III (IPR022683) 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 3.6e-05 in 251424 control chromosomes (gnomAD). c.1621C>T has been reported in the literature in multiple individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (e.g. Milic_2005, Piluso_2005, Tian_2015). These data indicate that the variant is very likely to be associated with disease. Seven ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic and one ClinVar submitter (evaluation after 2014) cites it as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.
Lifecell International Pvt. Ltd	RCV003222054	SCV003915941	likely pathogenic	Muscular dystrophy, limb-girdle, autosomal dominant 4		criteria provided, single submitter	clinical testing	A Heterozygous Missense variant c.1621C>T in Exon 13 of the CAPN3 gene that results in the amino acid substitution p.Arg541Trp was identified. The observed variant has a minor allele frequency of 0.00004% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting a greater likelihood that the variant is disease-causing. The variant has been reported to ClinVar as Conflicting interpretations of pathogenicityPathogenic(5); Likely pathogenic(1); Uncertain significance(1) with a status of (1 star) criteria provided, conflicting interpretations (Variation ID 498267 as of 2022-11-05). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 541 of the CAPN3 protein (p.Arg541Trp) (Milic A et al., 2005). Based on the above evidence this variant has been classified as Likely Pathogenic according to the ACMG guidelines.
Baylor Genetics	RCV003222054	SCV004213757	pathogenic	Muscular dystrophy, limb-girdle, autosomal dominant 4	2023-07-04	criteria provided, single submitter	clinical testing
Counsyl	RCV000595213	SCV000797507	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2018-01-30	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000595213	SCV002085529	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2020-12-14	no assertion criteria provided	clinical testing