ClinVar Miner

Submissions for variant NM_021098.3(CACNA1H):c.4120G>A (p.Val1374Met)

gnomAD frequency: 0.00018  dbSNP: rs201855332
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000517788 SCV000612581 uncertain significance not specified 2017-07-10 criteria provided, single submitter clinical testing
Invitae RCV000635008 SCV000756386 uncertain significance Idiopathic generalized epilepsy; Hyperaldosteronism, familial, type IV 2024-01-10 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 1374 of the CACNA1H protein (p.Val1374Met). This variant is present in population databases (rs201855332, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with CACNA1H-related conditions. ClinVar contains an entry for this variant (Variation ID: 446952). 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 CACNA1H protein function with a positive predictive value of 80%. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000517788 SCV004029623 uncertain significance not specified 2023-07-19 criteria provided, single submitter clinical testing Variant summary: CACNA1H c.4120G>A (p.Val1374Met) results in a conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00028 in 243392 control chromosomes (gnomAD). To our knowledge, no occurrence of c.4120G>A in individuals affected with Idiopathic Generalized Epilepsy and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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