Submissions for variant NM_000070.3(CAPN3):c.2120A>G (p.Asp707Gly)

gnomAD frequency: 0.00005  dbSNP: rs200379491

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000542626	SCV000645487	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 707 of the CAPN3 protein (p.Asp707Gly). This variant is present in population databases (rs200379491, gnomAD 0.2%). This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (PMID: 10567047, 11525884, 25252031, 26632398). 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: 468648). 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%. For these reasons, this variant has been classified as Pathogenic.
Eurofins Ntd Llc (ga)	RCV000723534	SCV000700548	pathogenic	not provided	2016-10-14	criteria provided, single submitter	clinical testing
NeuroMeGen, Hospital Clinico Santiago de Compostela	RCV000542626	SCV000882607	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2018-10-08	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000542626	SCV001163397	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A		criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000542626	SCV001194156	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2020-01-06	criteria provided, single submitter	clinical testing	NM_000070.2(CAPN3):c.2120A>G(D707G) is classified as pathogenic in the context of calpainopathy. Sources cited for classification include the following: PMID 25079074, 26632398, 11525884 and 27066573. Classification of NM_000070.2(CAPN3):c.2120A>G(D707G) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Medical Genetic Department, The Affiliated Hospital of Qingdao University	RCV000542626	SCV001468297	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2020-12-01	criteria provided, single submitter	research	The missense variant c.2120A>G/p.(Asp707Gly) in exon 20 resulted in a single-nucleotide polymorphism (A to G) at site 2120 in the coding region of CAPN3 (NM_000070.2), which introduced an aspartic acid residue that replaced a glycine in codon 707 (Fig. 3A). This variant was previously reported in multiple (>10) homozygous or compound heterozygous patients with LGMDs (PM3-PVS), which co-segregated within a family (PP1-PM). The normal population database includes this variant; its frequency is 0.0148% (42/282854, gnomAD) (PM2); bioinformatics analysis software SIFT, PolyPhen2, and Variant Taster consistently predicted the variant to be harmful (PP3). In addition, the variant is included in ClinVar as a “pathogenic/suspected pathogenic variant.” According to available evidence, the variant is defined as pathogenic (PM3-PVS+PM2+PP1-PM+PP3) based on the 2015 ACMG guidelines for sequence variant interpretation.The WES of this patient revealed compound heterozygous variants in CAPN3, c.2120A>G/p. (Asp707Gly) in exon 20 and c.2201_2202delAT/p.(Tyr734*) in exon 21, which were inherited from his parents and absent from 200 control individuals of similar ethnic origin, indicating that these variants are the pathogenic triggers of the LGMDR1 phenotype. In summary, we observed a sporadic male case of LGMDR1 and identified two compound heterozygous variants in CAPN3, namely c.2120A>G/p. (Asp707Gly) and c.2201_2202delAT/ p.(Tyr734*)), which co-segregated with the LGMDR1 phenotypes in the proband’s family.
Revvity Omics, Revvity	RCV000723534	SCV002018087	pathogenic	not provided	2019-02-08	criteria provided, single submitter	clinical testing
3billion	RCV000542626	SCV002059128	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2022-01-03	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000468648, PS1_S). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals(PMID: 26632398, PM3_S). A different missense change at the same codon has been reported to be associated with CAPN3 related disorder (ClinVar ID: VCV000290334, PM5_P).The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.966, 3CNET: 0.862, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000148, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Fulgent Genetics, Fulgent Genetics	RCV002476173	SCV002790399	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A; Muscular dystrophy, limb-girdle, autosomal dominant 4	2021-11-16	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003476296	SCV004211502	pathogenic	Muscular dystrophy, limb-girdle, autosomal dominant 4	2024-03-26	criteria provided, single submitter	clinical testing
GeneDx	RCV000723534	SCV005201650	pathogenic	not provided	2022-01-27	criteria provided, single submitter	clinical testing	Published functional studies demonstrate no detectable protein in the muscle tissue of a patient homozygous for this variant (PMID: 10567047); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 36066420, 25525159, 27363342, 30127231, 30919934, 10567047, 26632398, 31656265, 33899113, 25252031, 25079074, 32573981, 27066573, 34323405, 11525884, 27500519, 32994280, 35314707, 28403181)
Natera, Inc.	RCV000542626	SCV002085554	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2021-05-26	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004538015	SCV004118657	pathogenic	CAPN3-related disorder	2024-02-02	no assertion criteria provided	clinical testing	The CAPN3 c.2120A>G variant is predicted to result in the amino acid substitution p.Asp707Gly. This variant has been reported with a second CAPN3 variant or in the homozygous state in individuals with limb-girdle muscular dystrophy (see, for example, Minami et al. 1999. PubMed ID: 10567047; Chae et al. 2001. PubMed ID: 11525884; Park et al. 2016. PubMed ID: 26632398). This variant is reported in 0.21% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as pathogenic.