Submissions for variant NM_021098.3(CACNA1H):c.3804C>G (p.Ser1268Arg)

dbSNP: rs750607074

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV001334120	SCV001526866	uncertain significance	Epilepsy, childhood absence, susceptibility to, 6	2018-01-29	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004699314	SCV005204079	uncertain significance	not specified	2024-06-21	criteria provided, single submitter	clinical testing	Variant summary: CACNA1H c.3804C>G (p.Ser1268Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6e-06 in 166300 control chromosomes. 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.3804C>G in individuals affected with Idiopathic Generalized Epilepsy and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 1032114). Based on the evidence outlined above, the variant was classified as uncertain significance.
Neuberg Centre For Genomic Medicine, NCGM	RCV001334120	SCV005329642	uncertain significance	Epilepsy, childhood absence, susceptibility to, 6	2023-05-20	criteria provided, single submitter	clinical testing	The observed missense c.3804C>G(p.Ser1268Arg) variant in CACNA1H gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is present with an allele frequency of 0.0006% in gnomAD Exomes database. This variant has been submitted to the ClinVar database as Uncertain significance. Multiple lines of computational evidence (Polyphen - Benign, SIFT - Tolerated and MutationTaster - polymorphism) predict no damaging effect on protein structure and function for this variant. The amino acid change p.Ser1268Arg in CACNA1H is predicted as conserved by GERP++. The amino acid Ser at position 1268 is changed to a Arg changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Variant of Uncertain Significance(VUS).