Submissions for variant NM_005751.5(AKAP9):c.4342A>G (p.Ile1448Val)

gnomAD frequency: 0.00065  dbSNP: rs150379637

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000171718	SCV000055229	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
Ambry Genetics	RCV000243341	SCV000319038	likely benign	Cardiovascular phenotype	2018-06-22	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.
Invitae	RCV001082717	SCV000553480	likely benign	Long QT syndrome	2024-01-12	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488421	SCV004240966	benign	not specified	2023-12-12	criteria provided, single submitter	clinical testing	Variant summary: AKAP9 c.4342A>G (p.Ile1448Val) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00062 in 250104 control chromosomes, predominantly at a frequency of 0.001 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 300-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 a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.4342A>G in individuals affected with Long QT Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. The following publication has been ascertained in the context of this evaluation (PMID: 26671970). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign.
Clinical Genetics, Academic Medical Center	RCV000171718	SCV001922194	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000171718	SCV001951017	likely benign	not provided		no assertion criteria provided	clinical testing