ClinVar Miner

Submissions for variant NM_005751.5(AKAP9):c.2581T>C (p.Tyr861His)

gnomAD frequency: 0.00066  dbSNP: rs61757557
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health RCV000171715 SCV000050730 likely benign not provided 2013-06-24 criteria provided, single submitter research
Illumina Laboratory Services, Illumina RCV000264374 SCV000470219 uncertain significance Congenital long QT syndrome 2016-06-14 criteria provided, single submitter clinical testing
Ambry Genetics RCV000621677 SCV000737426 likely benign Cardiovascular phenotype 2019-04-30 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV002054028 SCV002492033 likely benign Long QT syndrome 2023-09-10 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000171715 SCV000280043 likely benign not provided 2016-11-15 no assertion criteria provided provider interpretation Given the limited case data and the frequency in samples unselected for long QT (1% of Finnish individuals) we consider this a variant likely benign. Di Resta et al (2015) identified this variant in one individual with Brugada syndrome. No individual phenotypic information was available, but the cohort consisted of 91 unrelated patients with Brugada syndrome on the basis of either type I ECG, spontaneous or induced by flecainide or ajmaline infusion and who were SCN5A-negative. It is a non-conservative amino acid substitution of a hydrophobic Tyrosine with a hydrophilic Histidine at a conserved residue. In silico analysis with PolyPhen2 predicts the variant is probably damaging. No other variants have been reported in this region of AKAP9. However, ExAC constraint analyses of AKAP9 appears to be tolerant to missense variation (Z= -2.75), as well as loss of function/truncating variation (pLI=0.00). The variant is listed in dbSNP (rs61757557). The ClinSeq group reported it in 1 of 854 individuals not selected for long QT syndrome (Ng et al 2013). The variant was reported online in a total of 217 of 138,602 individuals 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, Latino, and Ashkenazi descent. It was seen in 129 of 13,003 Finnish individuals (0.99%), 71 of 61,939 European individuals (0.11%), and 12 of 17,980 Latino individuals (0.06%).

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