Submissions for variant NM_000726.5(CACNB4):c.44C>G (p.Pro15Arg)

gnomAD frequency: 0.00201  dbSNP: rs200662010

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000186843	SCV000240414	uncertain significance	not specified	2015-12-09	criteria provided, single submitter	clinical testing	p.Pro15Arg (CCG>CGG): c.44 C>G in exon 1 of the CACNB4 gene (NM_000726.2). The P15R variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The NHLBI Exome Sequencing Project reports P15R was observed in 26/8128 (0.3%) alleles from individuals of European background, and the 1000 Genomes Project reports P15R was observed in 1/120 (0.8%) alleles from individuals of Mexican background, indicating it may be a rare (benign) variant in these populations. The P15R 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. However, this substitution alters a poorly conserved position in the predicted N-terminal region of the CACNB4 protein, and disease-associated mutations have not been reported in this region to date (Escayg et al., 2000; Ohmori et al., 2008). Additionally, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CHILD-EPI panel(s).
Genetic Services Laboratory, University of Chicago	RCV000186843	SCV000246840	likely benign	not specified	2019-04-22	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000186843	SCV000339595	likely benign	not specified	2016-02-08	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000384411	SCV000417257	likely benign	Juvenile myoclonic epilepsy	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000271279	SCV000417258	benign	Episodic ataxia type 5	2018-01-13	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.
Invitae	RCV000471900	SCV000562363	likely benign	Idiopathic generalized epilepsy	2023-10-11	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000515246	SCV000611379	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	RCV000515246	SCV000809097	uncertain significance	Epilepsy, idiopathic generalized, susceptibility to, 9; Episodic ataxia type 5	2018-06-18	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000186843	SCV001474893	benign	not specified	2020-08-12	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV002054189	SCV002496519	benign	not provided	2023-02-01	criteria provided, single submitter	clinical testing	CACNB4: BS1, BS2
PreventionGenetics, part of Exact Sciences	RCV004537572	SCV004742799	likely benign	CACNB4-related disorder	2020-04-06	criteria provided, single submitter	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).