Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001852195 | SCV002254887 | likely pathogenic | Episodic ataxia type 2; Developmental and epileptic encephalopathy, 42 | 2023-10-03 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1673 of the CACNA1A protein (p.Arg1673Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of CACNA1A-related conditions (PMID: 29056246). ClinVar contains an entry for this variant (Variation ID: 196769). 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 CACNA1A protein function. This variant disrupts the p.Arg1673 amino acid residue in CACNA1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28742085, 31015257). 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV002298504 | SCV002598684 | likely pathogenic | Developmental and epileptic encephalopathy, 42 | 2022-09-11 | criteria provided, single submitter | clinical testing | Variant summary: CACNA1A c.5017C>T (p.Arg1673Cys) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249260 control chromosomes. c.5017C>T has been reported in the literature in at-least one comprehensively genotyped individual affected with generalized convulsive epilepsy and hemiplegia who was screened on an epilepsy and seizure disorders panel of 110 genes (example, Butler_2017). These data do not allow firm conclusions about variant significance, however, a different variant, namely c.5018C>G (p.Arg1673Pro) has been reported as a de-novo occurence in an individual with global developmental delay and progressive cerebellar atrophy, with experimental evidence supporting a gain of function. This supports the critical relevance of this amino acid to overall function (Luo_2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Eurofins Ntd Llc |
RCV000177634 | SCV000229535 | uncertain significance | not provided | 2014-07-03 | flagged submission | clinical testing |