ClinVar Miner

Submissions for variant NM_005751.4(AKAP9):c.2370G>A (p.Met790Ile) (rs1298504605)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000552739 SCV000627722 uncertain significance Long QT syndrome 2017-05-12 criteria provided, single submitter clinical testing This sequence change replaces methionine with isoleucine at codon 790 of the AKAP9 protein (p.Met790Ile). The methionine residue is weakly conserved and there is a small physicochemical difference between methionine and isoleucine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a AKAP9-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a novel 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.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000786087 SCV000924722 uncertain significance not provided no assertion criteria provided provider interpretation AKAP9 Met790Ile AKAP9 c.2370G>A (p.Met790Ile) in exon 8; NM_005751.4; hg 19 chr7-91631601-G-A Given the limited data linking this gene to a phenotype that is different from that seen in our patient and the lack of case data for this variant, we consider this variant to be of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). We have seen this variant in a person with LVNC. Testing was ordered from Invitae. The variant has not been reported as disease-causing in the literature. Per the lab report, "The methionine residue is weakly conserved and there is a small physicochemical difference between methionine and isoleucine...Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies." The M790I variant was reported online in 1 of 122,431 individuals (MAF:0.0004%) in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 1 of 55,555 individuals of non-Finnish European descent (MAF=0.0009%). 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. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012). Another variant affecting the same codon, M790V was also reported in gnomAD in 2 of 137,640 people (MAF:0.0007%). Specifically, the variant was seen in 2 of 11,989 people (MAF: 0.008%) of African descent.

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