ClinVar Miner

Submissions for variant NM_001127221.1(CACNA1A):c.6470G>A (p.Arg2157His) (rs755749925)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000720430 SCV000851307 uncertain significance History of neurodevelopmental disorder 2016-10-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000493640 SCV000582269 uncertain significance not provided 2017-05-12 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the CACNA1A gene. The R2157H variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R2157H variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a position that is conserved across species. However, the R2157H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000692582 SCV000820412 uncertain significance Episodic ataxia type 2; Epileptic encephalopathy, early infantile, 42 2018-03-13 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 2157 of the CACNA1A protein (p.Arg2157His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. While this variant is present in population databases (rs755749925), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with CACNA1A-related disease. ClinVar contains an entry for this variant (Variation ID: 429650). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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