ClinVar Miner

Submissions for variant NM_001127221.1(CACNA1A):c.6467G>T (p.Arg2156Leu) (rs572722130)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000726322 SCV000343778 uncertain significance not provided 2016-08-11 criteria provided, single submitter clinical testing
GeneDx RCV000345600 SCV000528812 uncertain significance not specified 2017-10-24 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the CACNA1A gene. The R2156L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R2156L variantis observed in 1/1162 (0.09%) alleles from individuals of Ashkenazi Jewish background and 3/12,428 (0.02%) alleles from individuals of African background, including 1 homozygous individual undergoing testing at GeneDx (Lek et al., 2016). The R2156L 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 where amino acids with similar properties to Arginine are tolerated across species. 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 benignvariant.
Invitae RCV000556625 SCV000656790 uncertain significance Episodic ataxia type 2; Epileptic encephalopathy, early infantile, 42 2017-07-06 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 2156 of the CACNA1A protein (p.Arg2156Leu). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and leucine. While this variant is present in population databases (rs572722130), 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: 289416). 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: "Tolerated"; PolyPhen-2: "Possibly 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.
Ambry Genetics RCV000717822 SCV000848682 likely benign History of neurodevelopmental disorder 2017-06-19 criteria provided, single submitter clinical testing In silico models in agreement (benign);Does not segregate with disease in family study (genes with incomplete penetrance)
CeGaT Praxis fuer Humangenetik Tuebingen RCV000726322 SCV001151693 uncertain significance not provided 2019-05-01 criteria provided, single submitter clinical testing

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