Submissions for variant NM_005751.5(AKAP9):c.6556T>C (p.Ser2186Pro)

gnomAD frequency: 0.00250  dbSNP: rs76177450

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000171722	SCV000055232	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV001080872	SCV000261246	benign	Long QT syndrome	2024-01-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000243812	SCV000318603	likely benign	Cardiovascular phenotype	2018-09-07	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000624953	SCV000743175	likely benign	Long QT syndrome 11	2014-10-09	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000853018	SCV000995775	benign	Cardiomyopathy; Long QT syndrome	2019-04-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001328420	SCV001519542	benign	not specified	2021-03-11	criteria provided, single submitter	clinical testing	Variant summary: AKAP9 c.6556T>C (p.Ser2186Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0033 in 251434 control chromosomes in the gnomAD database, including 2 homozygotes. The observed variant frequency is approximately 1000-fold of the estimated maximal expected allele frequency for a pathogenic variant in AKAP9 causing Long QT Syndrome phenotype (3.3e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.6556T>C in individuals affected with Long QT Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (n=2) / likely benign (n=1). Based on the evidence outlined above, the variant was classified as benign.
Genome-Nilou Lab	RCV000624953	SCV002524853	benign	Long QT syndrome 11	2021-12-05	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000171722	SCV004164291	likely benign	not provided	2023-01-01	criteria provided, single submitter	clinical testing	AKAP9: BP4, BS2
Breakthrough Genomics, Breakthrough Genomics	RCV000171722	SCV005220995	likely benign	not provided		criteria provided, single submitter	not provided
Clinical Genetics, Academic Medical Center	RCV001328420	SCV001923486	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001328420	SCV001951958	benign	not specified		no assertion criteria provided	clinical testing