Submissions for variant NM_005751.5(AKAP9):c.5870A>G (p.Asn1957Ser)

gnomAD frequency: 0.00001  dbSNP: rs767966419

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001526965	SCV001737743	likely benign	not specified	2021-06-14	criteria provided, single submitter	clinical testing	Variant summary: AKAP9 c.5870A>G (p.Asn1957Ser) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 250918 control chromosomes, predominantly at a frequency of 0.0004 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 120 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 Latino origin. To our knowledge, no occurrence of c.5870A>G in individuals affected with Long QT Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001882570	SCV002163025	uncertain significance	Long QT syndrome	2021-08-14	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine with serine at codon 1957 of the AKAP9 protein (p.Asn1957Ser). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs767966419, ExAC 0.04%). This variant has not been reported in the literature in individuals affected with AKAP9-related conditions. ClinVar contains an entry for this variant (Variation ID: 1172874). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002359152	SCV002652681	uncertain significance	Cardiovascular phenotype	2021-12-16	criteria provided, single submitter	clinical testing	The p.N1957S variant (also known as c.5870A>G), located in coding exon 24 of the AKAP9 gene, results from an A to G substitution at nucleotide position 5870. The asparagine at codon 1957 is replaced by serine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear.