Submissions for variant NM_201596.3(CACNB2):c.873G>A (p.Leu291=)

gnomAD frequency: 0.00355  dbSNP: rs138423466

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000180025	SCV000232369	benign	not specified	2014-11-12	criteria provided, single submitter	clinical testing
Invitae	RCV000197803	SCV000252901	benign	Brugada syndrome 4	2024-01-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000248968	SCV000319062	likely benign	Cardiovascular phenotype	2015-09-15	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000180025	SCV001361009	benign	not specified	2019-05-27	criteria provided, single submitter	clinical testing	Variant summary: CACNB2 c.711G>A alters a conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0034 in 250822 control chromosomes in the gnomAD database, including 2 homozygotes. The observed variant frequency is approximately 339 fold of the estimated maximal expected allele frequency for a pathogenic variant in CACNB2 causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is benign. c.711G>A has been reported in the literature in patients with Autistic Spectrum Disorder (Breitenkamp_2014). This report however, does not provide unequivocal conclusions about association of the variant with Arrhythmia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (2x benign/likely benign and 1x uncertain significance). Based on the evidence outlined above, the variant was classified as benign.
GeneDx	RCV001711469	SCV001945250	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000197803	SCV002048161	likely benign	Brugada syndrome 4	2021-03-13	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001711469	SCV004126521	likely benign	not provided	2023-02-01	criteria provided, single submitter	clinical testing	CACNB2: BP4, BS2
Clinical Genetics, Academic Medical Center	RCV000180025	SCV001921623	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000180025	SCV001951114	benign	not specified		no assertion criteria provided	clinical testing