ClinVar Miner

Submissions for variant NM_001127222.2(CACNA1A):c.6400C>T (p.Arg2134Cys) (rs121908235)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000710089 SCV000329178 uncertain significance not provided 2018-11-29 criteria provided, single submitter clinical testing The R2135C variant in the CACNA1A gene has been reported, using alternate nomenclature R2136C, in an individual with episodic ataxia type 2 (Mantuano et al., 2004). The R2135C variant was not observed with any significant frequency in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project but the 1000 Genomes Project reports R2135C was observed in 1/198 alleles (0.51%) alleles from individuals of Northern European background in Utah (McVean et al., 2012). The R2135C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret R2135C as a variant of unknown significance.
Athena Diagnostics Inc RCV000710089 SCV000612565 uncertain significance not provided 2018-11-07 criteria provided, single submitter clinical testing
Invitae RCV000653342 SCV000775221 uncertain significance Episodic ataxia type 2; Epileptic encephalopathy, early infantile, 42 2019-10-07 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 2135 of the CACNA1A protein (p.Arg2135Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. While this variant is present in population databases (rs121908235), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported in an individual affected with typical episodic ataxia type 2 disease (PMID: 15173248). This variant is also known as c.6681C>T, p.R2136C in the literature. ClinVar contains an entry for this variant (Variation ID: 68440). 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: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Kariminejad - Najmabadi Pathology & Genetics Center RCV000788079 SCV000927077 uncertain significance Cerebellar ataxia 2018-11-22 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000710089 SCV001151695 uncertain significance not provided 2019-04-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001174863 SCV001338254 uncertain significance not specified 2020-02-11 criteria provided, single submitter clinical testing Variant summary: CACNA1A c.6403C>T (p.Arg2135Cys) results in a non-conservative amino acid change located in the C-terminal tail, upstream of the polyglutamine repeat (Mantuano_2004). The CACNA1A gene has a bicistronic mRNA, with the first cistron encoding the voltage-gated calcium channel subunit alpha1A and the second cistron expressing a transcription factor, alpha1ACT (that also contains the polyglutamine tract), which coordinates the expression of genes involved in neural and Purkinje cell development (PMID: 23827678); our variant of interest affects both of the encoded proteins. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.1e-05 in 97896 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6403C>T has been reported in the literature in individuals affected with Episodic ataxia type 2 and Huntington disease (Mantuano_2004, Mariani_2016). These reports do not provide unequivocal conclusions about association of the variant with Episodic ataxia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
UniProtKB/Swiss-Prot RCV000059310 SCV000090871 not provided Episodic ataxia type 2 no assertion provided not provided

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