Submissions for variant NM_005751.5(AKAP9):c.8677G>C (p.Asp2893His)

gnomAD frequency: 0.00025  dbSNP: rs142573103

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000529741	SCV000627763	uncertain significance	Long QT syndrome	2023-12-20	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 2893 of the AKAP9 protein (p.Asp2893His). This variant is present in population databases (rs142573103, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. 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: 457126). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.
GeneDx	RCV000786278	SCV001886620	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002448630	SCV002683358	benign	Cardiovascular phenotype	2023-11-21	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786278	SCV000925035	uncertain significance	not provided	2018-02-06	no assertion criteria provided	provider interpretation	Found in a 23-year-old female with unexplained postpartum sudden cardiac arrest, along with 5 other VUSs. p.Asp2893His (c.8677G>C) in exon 34 of the AKAP9 gene (NM_005751.4; ENST00000356239.7) Chromosome location 7:91713984 G / C Based on the information reviewed below, including the lack of case data and its prevalence in population databases, we classify it as a Variant of Uncertain Significance (VUS), probably benign, concluding that there is not sufficient evidence for its pathogenicity to warrant using it for diagnosis or predictive genetic testing. This variant has not been reported in the literature in association with disease, according to the Invitae report. This is a nonconservative amino acid change, resulting in the replacement of a negatively-charged Aspartic Acid with a positively-charged Histidine. Aspartic Acid at this location is poorly conserved across ~100 vertebrate species for which we have data. There are no Likely Pathogenic or Pathogenic variants listed in ClinVar within 10 amino acids to either side, indicating that this region of the protein might be tolerant of change. According to the Invitae report, algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant was reported in 20 individuals in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Overall MAF: 0.007%. Invitae reports that it has an allele count higher than expected for a pathogenic variant. Of note: Whiffin et al (2017) proposed that variants with frequency greater than 0.0008% are unlikely to be pathogenic for LQTS. This variant was observed in 15 African-ancestry individuals (for the highest allele frequency: 0.06%) and 5 Latinos, (MAF 0.01%). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases. Our patient's ancestry is Latino.