ClinVar Miner

Submissions for variant NM_000070.3(CAPN3):c.1466G>A (p.Arg489Gln)

gnomAD frequency: 0.00016  dbSNP: rs147764579
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000517354 SCV000344033 pathogenic not provided 2018-02-09 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000517354 SCV000612633 pathogenic not provided 2017-04-28 criteria provided, single submitter clinical testing
GeneDx RCV000517354 SCV000616671 pathogenic not provided 2019-05-21 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect where normal autocatalytic calpain-3 activity was lost (Fanin et al., 2003); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in two families from Reunion Island with LGMD and observed in an additional patient with LGMD who harbored a pathogenic variant on the opposite allele (in trans) in published literature (Richard et al., 1999; Fanin et al., 2003); This variant is associated with the following publications: (PMID: 16884488, 16971480, 17236769, 10330340, 14578192, 17994539, 15221789, 18854869, 30919934, 32668095)
Invitae RCV000350336 SCV001236695 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2A 2024-01-24 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 489 of the CAPN3 protein (p.Arg489Gln). This variant is present in population databases (rs147764579, gnomAD 0.03%). This missense change has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy (LGMD) (PMID: 14578192, 17236769, 30919934). ClinVar contains an entry for this variant (Variation ID: 289644). 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 not expected to disrupt CAPN3 protein function with a negative predictive value of 80%. This variant disrupts the p.Arg489 amino acid residue in CAPN3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9762961, 16141003, 25135358, 27708273). 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.
CeGaT Center for Human Genetics Tuebingen RCV000517354 SCV001247170 pathogenic not provided 2018-05-01 criteria provided, single submitter clinical testing
Revvity Omics, Revvity Omics RCV000517354 SCV002025061 pathogenic not provided 2023-12-07 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002504018 SCV002800999 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2A; Muscular dystrophy, limb-girdle, autosomal dominant 4 2021-10-08 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002509353 SCV002819423 pathogenic Autosomal recessive limb-girdle muscular dystrophy 2022-12-11 criteria provided, single submitter clinical testing Variant summary: CAPN3 c.1466G>A (p.Arg489Gln) results in a conservative amino acid change located in the Peptidase C2, calpain, large subunit, domain III (IPR022682) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 251278 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CAPN3 causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (5.6e-05 vs 0.0032), allowing no conclusion about variant significance. c.1466G>A has been reported in the literature in multiple individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (example, Milic_2007, Bevilacqua_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Preventiongenetics, part of Exact Sciences RCV003401270 SCV004119057 pathogenic CAPN3-related condition 2023-02-20 criteria provided, single submitter clinical testing The CAPN3 c.1466G>A variant is predicted to result in the amino acid substitution p.Arg489Gln. This variant has been repeatedly reported in the compound heterozygous or homozygous state in individuals with limb-girdle muscular dystrophy (Richard et al. 1999. PubMed ID: 10330340; Fanin et al. 2003. PubMed ID: 14578192; Supp. Table 1 in Ten Dam et al. 2019. PubMed ID: 30919934; https://databases.lovd.nl/shared/genes/CAPN3). Functional studies indicate this variant disrupts the normal autocatalytic activity (Fanin et al. 2003. PubMed ID: 14578192). This variant is reported in 0.028% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-42693950-G-A). This variant is interpreted as pathogenic.
Baylor Genetics RCV003475920 SCV004211504 pathogenic Muscular dystrophy, limb-girdle, autosomal dominant 4 2023-10-28 criteria provided, single submitter clinical testing
Counsyl RCV000350336 SCV000798519 likely pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2A 2018-03-15 no assertion criteria provided clinical testing
GeneReviews RCV000350336 SCV002015204 not provided Autosomal recessive limb-girdle muscular dystrophy type 2A no assertion provided literature only
Natera, Inc. RCV000350336 SCV002085514 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2A 2020-03-26 no assertion criteria provided clinical testing

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