ClinVar Miner

Submissions for variant NM_021098.3(CACNA1H):c.1429C>T (p.Arg477Cys)

gnomAD frequency: 0.00018  dbSNP: rs376935647
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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 RCV000981765 SCV001129765 likely benign Idiopathic generalized epilepsy; Hyperaldosteronism, familial, type IV 2024-02-15 criteria provided, single submitter clinical testing
Ambry Genetics RCV002548458 SCV003565105 uncertain significance Inborn genetic diseases 2022-03-29 criteria provided, single submitter clinical testing The c.1429C>T (p.R477C) alteration is located in exon 9 (coding exon 8) of the CACNA1H gene. This alteration results from a C to T substitution at nucleotide position 1429, causing the arginine (R) at amino acid position 477 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City RCV001028016 SCV001190780 uncertain significance Epilepsy, childhood absence, susceptibility to, 6 2020-02-05 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001354189 SCV001548737 uncertain significance not provided no assertion criteria provided clinical testing  The CACNA1H p.R477C variant was not identified in the literature, however it was identified in dbSNP (ID: rs376935647) and in ClinVar (classified as likely benign by Invitae and uncertain significance by Biochemical Molecular Genetic Laboratory at King Abdulaziz Medical City for the associated conditions idiopathic generalized epilepsy and Hyperaldosteronism, familial, type IV). The variant was identified in control databases in 30 of 186924 chromosomes at a frequency of 0.0001605 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 23 of 8808 chromosomes (freq: 0.002611), Other in 3 of 5492 chromosomes (freq: 0.000546), European (non-Finnish) in 3 of 75540 chromosomes (freq: 0.00004) and Latino in 1 of 25726 chromosomes (freq: 0.000039), but was not observed in the African, East Asian, European (Finnish), or South Asian populations. The p.R477 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
PreventionGenetics, part of Exact Sciences RCV004535999 SCV004744724 likely benign CACNA1H-related disorder 2020-05-19 no assertion criteria provided clinical testing This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

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