ClinVar Miner

Submissions for variant NM_001127222.2(CACNA1A):c.6193G>A (p.Val2065Met)

gnomAD frequency: 0.00003  dbSNP: rs776203885
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001326413 SCV001517443 uncertain significance Episodic ataxia type 2; Developmental and epileptic encephalopathy, 42 2023-08-17 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 2066 of the CACNA1A protein (p.Val2066Met). This variant is present in population databases (rs776203885, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with CACNA1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 1026015). 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 not expected to disrupt CACNA1A protein function. 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.
GeneDx RCV001569193 SCV001793220 uncertain significance not provided 2024-06-17 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; Has not been previously published as pathogenic or benign to our knowledge
Athena Diagnostics RCV001569193 SCV002770754 uncertain significance not provided 2021-11-24 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003331116 SCV004037879 uncertain significance not specified 2023-08-04 criteria provided, single submitter clinical testing Variant summary: CACNA1A c.6196G>A (p.Val2066Met) results in a conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 248472 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.6196G>A in individuals affected with Epileptic Encephalopathy, Early Infantile, 42 and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Breakthrough Genomics, Breakthrough Genomics RCV001569193 SCV005192620 uncertain significance not provided criteria provided, single submitter not provided

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