Submissions for variant NM_021098.3(CACNA1H):c.5206C>T (p.Arg1736Cys)

dbSNP: rs750143885

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001979328	SCV002256708	uncertain significance	Idiopathic generalized epilepsy; Hyperaldosteronism, familial, type IV	2022-08-16	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 1465278). This variant has not been reported in the literature in individuals affected with CACNA1H-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1736 of the CACNA1H protein (p.Arg1736Cys).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987948	SCV004804159	uncertain significance	not specified	2024-01-04	criteria provided, single submitter	clinical testing	Variant summary: CACNA1H c.5206C>T (p.Arg1736Cys) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 244482 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5206C>T has been reported in the literature as heterozygous in at least one individual affected with classical trigeminal neuralgia type 2 (e.g. Dong_2020). However, this report does not provide unequivocal conclusions about association of the variant with Idiopathic Generalized Epilepsy. At least one publication reports experimental evidence evaluating an impact on protein function (e.g. Mustafa_2022). These results showed no damaging effect of this variant on electrical activation and inactivation properties in vitro compared to wild-type. The following publications have been ascertained in the context of this evaluation (PMID: 33083721, 36397158). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV004591668	SCV005078084	uncertain significance	not provided	2023-04-06	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; A published functional study did not demonstrate a damaging effect (Mustaf et al. 2022); Observed in an individual with trigeminal neuralgia in published literature (Dong et al., 2020); This variant is associated with the following publications: (PMID: 33083721, 36397158)