ClinVar Miner

Submissions for variant NM_005751.4(AKAP9):c.11525C>T (p.Ser3842Phe) (rs936516286)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000631717 SCV000752804 uncertain significance Long QT syndrome 2017-11-27 criteria provided, single submitter clinical testing This sequence change replaces serine with phenylalanine at codon 3842 of the AKAP9 protein (p.Ser3842Phe). The serine residue is highly conserved and there is a large physicochemical difference between serine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with AKAP9-related disease. 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000786088 SCV000924723 uncertain significance not provided 2018-01-25 no assertion criteria provided provider interpretation Found in a child whose mother had Filipino ancestry and a sudden cardiac death event at a young age, along with a VUS in RYR2. p.Ser3842Phe (c.11525C>T) in exon 48 of the AKAP9 gene (NM_005751.4) Chromosome location 7:91736715 C / T Based on the information reviewed below, we classify this as a Variant of Uncertain Significance. It is rare and is a significant change to a highly conserved amino acid, which could make it a good candidate to be disease-causing. It is reported in one East Asian individual in population databases, so it could also be a rare benign variant in this ancestry population. Our patient does have Filipino ancestry. To date, this patient has had normal QTc intervals and did not show QTc prolongation with exercise testing. According to the Invitae report, this variant has not previously been reported in the literature in association with disease. This is a nonconservative amino acid change, resulting in the replacement of a polar Serine with a nonpolar Phenylalanine. Serine at this location is highly conserved across ~100 vertebrate species for which we have data (it is instead a Cysteine in one species). The adjacent residues are also highly conserved. There are currently no Likely Pathogenic or Pathogenic missense variants listed in ClinVar within 10 amino acids to either side. 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). This variant was reported in 1 East Asian individual in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. There is good coverage at this site. 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 Filipino and Caucasian.

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