ClinVar Miner

Submissions for variant NM_005751.4(AKAP9):c.3580G>A (p.Ala1194Thr) (rs139965373)

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Total submissions: 9
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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 RCV000171716 SCV000050734 likely benign not provided 2013-06-24 criteria provided, single submitter research
Invitae RCV000233886 SCV000289088 benign Long QT syndrome 2019-12-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000302445 SCV000470234 uncertain significance Romano-Ward syndrome 2016-06-14 criteria provided, single submitter clinical testing
Ambry Genetics RCV000621526 SCV000735794 likely benign Cardiovascular phenotype 2019-02-25 criteria provided, single submitter clinical testing Subpopulation frequency in support of benign classification
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000171716 SCV000884995 uncertain significance not provided 2018-03-25 criteria provided, single submitter clinical testing The AKAP9 c.3580G>A; p.Ala1194Thr variant (rs139965373, ClinVar variant ID 180262) has been detected in large whole-exome datasets from a cohort of SIDS patients (Neubauer 2017) and an unselected population (Ng 2013). This variant is listed in the genome Aggregation Database (gnomAD) with an overall population frequency of 0.06% (identified on 159 out of 276,956 chromosomes, including one homozygote). The alanine at position 1194 is highly conserved, considering 11 species, and computational analyses of the effects of the p.Ala1194Thr variant on protein structure and function predict a deleterious effect (SIFT: damaging, PolyPhen-2: possibly damaging). Based on the available information, the clinical significance of the p.Ala1194Thr variant cannot be determined with certainty.
Integrated Genetics/Laboratory Corporation of America RCV001192969 SCV001361462 likely benign not specified 2019-11-18 criteria provided, single submitter clinical testing Variant summary: AKAP9 c.3580G>A (p.Ala1194Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00061 in 251174 control chromosomes, predominantly at a frequency of 0.00095 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 95 fold of the estimated maximal expected allele frequency for a pathogenic variant in AKAP9 causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.3580G>A has been reported in the literature in individuals affected with Sudden infant death syndrome, Hypertrophic Cardiomyopathy and prostate cancer (Neubauer_2017, Forleo_2017, Belic_2018). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmia. Additionally, co-occurrences with other pathogenic variants have been reported (MYBPC3 c.506-2A>C; BRCA2 c.4091_4092insAA, p.I1364fs) (Forleo_2017, Belic_2018), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as benign (1x) and uncertain significance (5x). Based on the evidence outlined above, the variant was classified as likely benign.
Blueprint Genetics RCV000157101 SCV000206824 likely benign Ventricular fibrillation 2014-05-26 no assertion criteria provided clinical testing
Division of Human Genetics,Children's Hospital of Philadelphia RCV000477762 SCV000536748 uncertain significance Long QT syndrome 11 2015-09-30 no assertion criteria provided research
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000171716 SCV000925031 uncertain significance not provided 2016-05-17 no assertion criteria provided provider interpretation

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