Submissions for variant NM_000070.3(CAPN3):c.2243G>A (p.Arg748Gln)

gnomAD frequency: 0.00002  dbSNP: rs587780290

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000116542	SCV000150495	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2013-11-07	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000489478	SCV000255661	pathogenic	not provided	2024-02-07	criteria provided, single submitter	clinical testing	This variant has been identified in multiple individuals with autosomal recessive Limb-girdle muscular dystrophy and segregates with disease in multiple families. The frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant segregates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 19226146, 22006685)
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	RCV000116542	SCV000267239	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2016-03-18	criteria provided, single submitter	reference population
Eurofins Ntd Llc (ga)	RCV000489478	SCV000331504	pathogenic	not provided	2017-11-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000489478	SCV000577258	pathogenic	not provided	2024-07-18	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18563459, 19364062, 10330340, 9762961, 22443334, 926673, 27234031, 36066420, 30056071, 19226146, 21204801, 22006685, 25525159, 27020652, 25987458, 18854869, 15689361, 9150160, 30028523, 30919934, 31589614, 34426522, 32528171, 35314707, 31069529, 35169782, 35723113, 25512505, 31980526, 32668095, 32403337, 37526466, 38374194)
Fulgent Genetics, Fulgent Genetics	RCV000116542	SCV000611185	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2017-05-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000116542	SCV000645491	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2024-10-30	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 748 of the CAPN3 protein (p.Arg748Gln). This variant is present in population databases (rs587780290, gnomAD 0.01%). This missense change has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy (PMID: 9150160, 9762961, 9777948, 10330340, 12461690, 15689361, 18563459, 18854869, 19015733, 22443334, 26404900, 27020652, 30028523). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 128570). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt CAPN3 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects CAPN3 function (PMID: 19226146). For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000116542	SCV001164496	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2018-12-03	criteria provided, single submitter	research	The homozygous p.Arg748Gln variant in CAPN3 was identified by our study in one individual with limb-girdle muscular dystrophy (LGMD) This variant has been identified in 0.01455% (5/34372) of Latino chromosomes and 0.004166% (1/24006) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs587780290). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. One study that examined a rat model with an analagous protein suggested that this variant affects protein catalytic activity (PMID: 19226146). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enought to determine pathogenicity. The p.Arg748Gln variant in CAPN3 has been reported in many individuals with LGMD in the homozygous and compound heterozygous states in ClinVar and the literature (Variation ID: 128570). This variant segregated with disease in 2 affected relatives from 1 family (PMID: 9150160). There are many reports of individuals with LGMD and this variant (in either the homozygous or compound heterozygous state) in ClinVar and the literature. Animal models in rats have shown that this variant causes LGMD via a deleterious effect on calpain protein catalytic activity (PMID: 19226146). In summary, the p.Arg748Gln variant is pathogenic based off of our findings, multiple reports in ClinVar, and the literature. ACMG/AMP Criteria applied: PM2, PP3, PS3, PP1, PM3_Strong (Richards 2015).
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001814062	SCV001755099	pathogenic	Abnormality of the musculature	2021-07-10	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000489478	SCV001961493	pathogenic	not provided	2021-09-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000489478	SCV002018064	pathogenic	not provided	2021-10-01	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000116542	SCV004047427	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2023-07-22	criteria provided, single submitter	clinical testing	The observed missense c.2243G>A p.Arg748Gln variant in CAPN3 gene has been previously reported in homozygous/ compound heterozygous states in multiple individuals affected with autosomal recessive limb-girdle muscular dystrophy Arrigoni et al., 2018; Fadaee et al., 2016; Hauerslev et al., 2012; Sáenz et al., 2011; Fanin et al., 2009. It has also been observed to segregate with disease in related individuals Fadaee et al., 2013; Richard et al., 1997. Experimental studies have shown that this missense change affects CAPN3 function Garnham et al., 2009. This variant is present with allele frequency of 0.002% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Likely Pathogenic/ Pathogenic multiple submissions. Multiple lines of computational evidence Polyphen - Probably Damaging, SIFT - Damaging and MutationTaster - Disease causing predict a damaging effect on protein structure and function for this variant. The reference amino acid of p.Arg748Gln in CAPN3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 748 is changed to a Gln changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV003474720	SCV004211554	pathogenic	Muscular dystrophy, limb-girdle, autosomal dominant 4	2024-03-13	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005008017	SCV005637815	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A; Muscular dystrophy, limb-girdle, autosomal dominant 4	2024-03-04	criteria provided, single submitter	clinical testing
Counsyl	RCV000116542	SCV000795867	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2017-11-21	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000116542	SCV001456373	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2020-09-16	no assertion criteria provided	clinical testing