Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000459803 | SCV000553475 | uncertain significance | Long QT syndrome | 2016-11-18 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine with glutamine at codon 3294 of the AKAP9 protein (p.Arg3294Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). The glutamine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. This variant is present in population databases (rs752685614, ExAC 0.03%) but has not been reported in the literature in individuals with a AKAP9-related disease. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003155193 | SCV003844795 | likely benign | not specified | 2023-02-15 | criteria provided, single submitter | clinical testing | Variant summary: AKAP9 c.9881G>A (p.Arg3294Gln) 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 4e-05 in 251344 control chromosomes (gnomAD). The observed variant frequency is approximately 12 fold of the estimated maximal expected allele frequency for a pathogenic variant in AKAP9 causing Long QT Syndrome (3.3e-06), strongly suggesting that the variant is benign. c.9881G>A has been reported in the literature occuring in a cohort of individuals who had Sudden Unexplained Death (Lin_2017). This report does not provide unequivocal conclusions about association of the variant with Long QT Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters have assessed the variant since 2014: both classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. |
| Ambry Genetics | RCV004022894 | SCV005023957 | benign | Cardiovascular phenotype | 2024-01-17 | 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, |
RCV000786277 | SCV000925033 | uncertain significance | not provided | 2016-11-18 | no assertion criteria provided | provider interpretation |