Submissions for variant NM_002234.4(KCNA5):c.381C>T (p.Ser127=)

gnomAD frequency: 0.02823  dbSNP: rs45504599

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000555990	SCV000379697	likely benign	Atrial fibrillation, familial, 7	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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000555990	SCV000646991	benign	Atrial fibrillation, familial, 7	2024-02-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000555990	SCV001473228	benign	Atrial fibrillation, familial, 7	2023-09-30	criteria provided, single submitter	clinical testing
GeneDx	RCV001675792	SCV001894001	benign	not provided	2020-09-23	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 28768485, 24068186, 15735608)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001699303	SCV003929277	benign	not specified	2023-04-05	criteria provided, single submitter	clinical testing	Variant summary: KCNA5 c.381C>T alters a non-conserved nucleotide resulting in a synonymous change. 4/4 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 0.026 in 249732 control chromosomes in the gnomAD database, including 115 homozygotes. The observed variant frequency is approximately 275-fold of the estimated maximal expected allele frequency for a pathogenic variant in KCNA5 causing Atrial Fibrillation phenotype (9.4e-05), strongly suggesting that the variant is benign. c.381C>T has been reported in the literature in individuals affected with Atrial Fibrillation or pulmonary arterial hypertension without evidence of causality and with other co-occurring variants (Winkel_2011, Wang_2016). These reports do not provide unequivocal conclusions about association of the variant with Atrial Fibrillation. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Breakthrough Genomics, Breakthrough Genomics	RCV001675792	SCV005213622	likely benign	not provided		criteria provided, single submitter	not provided
Clinical Genetics, Academic Medical Center	RCV001699303	SCV001918879	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001699303	SCV001956802	benign	not specified		no assertion criteria provided	clinical testing