ClinVar Miner

Submissions for variant NM_021098.3(CACNA1H):c.455TCA[1] (p.Ile153del)

dbSNP: rs775597863
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001888792 SCV002149493 uncertain significance Idiopathic generalized epilepsy; Hyperaldosteronism, familial, type IV 2021-04-26 criteria provided, single submitter clinical testing This variant is present in population databases (rs775597863, ExAC 0.007%). This variant, c.458_460del, results in the deletion of 1 amino acid(s) of the CACNA1H protein (p.Ile153del), but otherwise preserves the integrity of the reading frame. 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. Experimental studies have shown that this variant affects CACNA1H protein function (PMID: 32143681). This variant has been observed in individual(s) with clinical features of amyotrophic lateral sclerosis (PMID: 32143681).
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center RCV004784002 SCV005397736 uncertain significance Epilepsy, childhood absence, susceptibility to, 6 2024-05-10 criteria provided, single submitter clinical testing This sequence variant is a three nucleotide substitution (delTCA) at position 458_460 of the coding sequence of the CACNA1H gene that results in the deletion of the isoleucine residue at position 153 of the calcium voltage-gated channel subunit alpha1 H protein. The 153 residue occurs in the second transmembrane region of the calcium voltage-gated channel subunit alpha1 H protein (PMID: 31217264, 32143681). This is a previously reported variant (ClinVar 1385377) that has been observed in individual affected by global developmental delay and autism spectrum disorder (PMID: 38539105) and an individual affected by amyotrophic lateral sclerosis (PMID: 32143681). This variant is present in 2 of 350142 alleles (0.0006%) in the gnomAD population dataset. Predictions from bioinformatic tools are inconclusive for this variant. Functional studies in human cells indicate that the protein resulting from this variant disrupts Cav3.2 channel function possibly through the rapid degradation of the protein (PMID: 32143681). However additional studies are needed to verify this observation. Based upon the evidence, we consider this a variant of uncertain significance. ACMG Criteria: PM2, PM4, PS3

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