ClinVar Miner

Submissions for variant NM_000070.3(CAPN3):c.1202A>G (p.Tyr401Cys)

gnomAD frequency: 0.00002  dbSNP: rs371784007
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000668931 SCV000793609 uncertain significance Autosomal recessive limb-girdle muscular dystrophy type 2A 2017-08-30 criteria provided, single submitter clinical testing
Eurofins Ntd Llc (ga) RCV000728828 SCV000856445 uncertain significance not provided 2017-08-22 criteria provided, single submitter clinical testing
Invitae RCV000668931 SCV002186876 likely pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2A 2023-12-02 criteria provided, single submitter clinical testing This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 401 of the CAPN3 protein (p.Tyr401Cys). This variant is present in population databases (rs371784007, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of autosomal recessive limb-girdle muscular dystrophy (PMID: 15689361, 19556129, 27066573). ClinVar contains an entry for this variant (Variation ID: 553468). 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%. This variant disrupts the p.Tyr401 amino acid residue in CAPN3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 33337384; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Fulgent Genetics, Fulgent Genetics RCV002507166 SCV002815453 uncertain significance Autosomal recessive limb-girdle muscular dystrophy type 2A; Muscular dystrophy, limb-girdle, autosomal dominant 4 2021-11-09 criteria provided, single submitter clinical testing
GeneDx RCV000728828 SCV004012481 likely pathogenic not provided 2023-06-14 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); 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: 27066573, 15689361, 19556129)

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