Submissions for variant NM_000726.5(CACNB4):c.5C>T (p.Ser2Phe)

gnomAD frequency: 0.00091  dbSNP: rs200092211

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000724000	SCV000224258	uncertain significance	not provided	2014-08-13	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000195021	SCV000246842	uncertain significance	not specified	2015-08-04	criteria provided, single submitter	clinical testing
GeneDx	RCV000724000	SCV000329192	uncertain significance	not provided	2017-12-12	criteria provided, single submitter	clinical testing	The S2F variant of unknown significance has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The 1000 Genomes Project reports S2F was observed in 1/214 alleles (0.5%) from individuals of Italian background (McVean et al., 2012). The S2F variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution alters a highly conserved position in the N-terminal region of the CACNB4 protein, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, to date only a small number of substitutions in CACNB4 have been published in association with epilepsy, and no pathogenic variants have been reported in the N-terminal region of the protein (Escayg et al., 2000; Ohmori et al., 2008). Therefore, based on the currently available information, it is unclear whether S2F is a pathogenic or a rare benign variant.
Illumina Laboratory Services, Illumina	RCV000286296	SCV000417261	benign	Episodic ataxia type 5	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV000341315	SCV000417262	likely benign	Juvenile myoclonic epilepsy	2016-06-14	criteria provided, single submitter	clinical testing
Invitae	RCV001079683	SCV000562362	likely benign	Idiopathic generalized epilepsy	2022-11-22	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000515346	SCV000611380	uncertain significance	Epilepsy, idiopathic generalized, susceptibility to, 9; Episodic ataxia type 5	2017-05-23	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000660363	SCV000782433	uncertain significance	Epilepsy, idiopathic generalized, susceptibility to, 9	2016-03-31	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000195021	SCV001880099	benign	not specified	2021-04-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000724000	SCV004147033	benign	not provided	2022-10-01	criteria provided, single submitter	clinical testing	CACNB4: BS1, BS2
PreventionGenetics, part of Exact Sciences	RCV004535183	SCV004741901	benign	CACNB4-related disorder	2019-11-26	criteria provided, single submitter	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000724000	SCV001930896	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000724000	SCV001966595	likely benign	not provided		no assertion criteria provided	clinical testing