Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000552739 | SCV000627722 | uncertain significance | Long QT syndrome | 2022-03-23 | criteria provided, single submitter | clinical testing | This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 790 of the AKAP9 protein (p.Met790Ile). This variant is present in population databases (no rsID available, gnomAD 0.0009%). 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: 457092). 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. 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 | RCV004629235 | SCV005123209 | likely benign | Cardiovascular phenotype | 2024-04-18 | criteria provided, single submitter | clinical testing | This alteration is classified as likely 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, |
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. |