ClinVar Miner

Submissions for variant NM_000070.3(CAPN3):c.2148G>T (p.Glu716Asp) (rs770894443)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000644995 SCV000800734 uncertain significance Limb-girdle muscular dystrophy, type 2A 2017-10-07 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000412799 SCV000338311 likely pathogenic not provided 2018-03-05 criteria provided, single submitter clinical testing
GeneDx RCV000412799 SCV000491159 pathogenic not provided 2017-05-31 criteria provided, single submitter clinical testing The E716D missense variant has been reported previously in a patient with LGMD2A who also harbored a second CAPN3 variant; however phase was undetermined (Saenz et al., 2005). Functional studies demonstrate a complete loss of the CAPN3 protein in this patient (Saenz et al., 2005). The E716D variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The E716D variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species. Additionally, a missense variant in a nearby residue (L712F) has been reported in the Human Gene Mutation Database in association with LGMD (Stenson et al., 2014). Therefore, we interpret E716D as a pathogenic variant.
Invitae RCV000644995 SCV000766732 uncertain significance Limb-girdle muscular dystrophy, type 2A 2018-07-19 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with aspartic acid at codon 716 of the CAPN3 protein (p.Glu716Asp). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been reported in combination with a pathogenic variant in the CAPN3 gene in an individual affected with limb girdle muscular dystrophy that showed total loss of CAPN3 protein in skeletal muscle (PMID: 15689361). ClinVar contains an entry for this variant (Variation ID: 285340). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C35"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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