Submissions for variant NM_005751.5(AKAP9):c.510G>C (p.Glu170Asp)

gnomAD frequency: 0.00212  dbSNP: rs144888041

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000170646	SCV000050735	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
GeneDx	RCV000170646	SCV000223198	uncertain significance	not provided	2012-02-23	criteria provided, single submitter	clinical testing	p.E170D:GAG>GAC at the protein level, c.510 G>C at the DNA level. A heterozygous G>C nucleotide substitution was identified in exon 6 of the AKAP9 gene, resulting in replacement of the normal Glutamic acid codon (GAG) with an Aspartic acid codon (GAC) at amino acid position 170 in the A-kinase anchor protein 9. This missense change is denoted Glu170Asp (aka E170D) at the protein level and c.510 G>C at the cDNA level. The Glu170Asp variant in the AKAP9 gene has not been previously reported as a disease-causing mutation nor as a benign polymorphism, to our knowledge. The Glu170Asp variant was not detected in 600 alleles from control individuals of Caucasian and African American ancestry tested at GeneDx, indicating it is not a common benign variant in these populations. However, Glu170Asp results in a conservative substitution of a negatively charged amino acid with another at a position that is not highly conserved across species. In addition, no missense mutations have been reported in nearby codons of the AKAP9 gene, and Glu170Asp does not occur in or near either of the two known binding sites of AKAP9, indicating this region of the protein may be tolerant of change. With the molecular and clinical information available, we cannot determine the clinical significance of Glu170Asp and classify it as a variant of unknown clinical significance at this time. The variant is found in LQT panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000197421	SCV000253473	benign	Long QT syndrome	2025-02-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000242948	SCV000318720	likely benign	Cardiovascular phenotype	2018-11-09	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.
Illumina Laboratory Services, Illumina	RCV000354957	SCV000470198	uncertain significance	Congenital long QT syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV000584786	SCV000692522	benign	Brugada syndrome 1	2017-03-16	criteria provided, single submitter	research	The AKAP9 Glu170Asp has been previously identified in a Marfan Syndrome case, the patient also carried a FBN1 Cys2592Arg variant (Garzon SS, 2015). The AKAP9 Glu170Asp variant is found at high frequency in the Exome Aggregation Consortium dataset (MAF= 0.002; http://exac.broadinstitute.org/), suggesting that it is a common polymorphism (Ng D, et al., 2013). We identified this variant in one proband with Brugada syndrome, who has no family history of disease or SCD. The proband also carries a rare variant (RYR2 Asp1412Gly). Furthermore, computational tools SIFT, MutationTaster, and PolyPhen-2 predict this variant to be well tolerated. Based on a high allele frequency in the general population and in silico tools predicting no deleterious affect on the protein, we classify this variant as "benign".
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000624949	SCV000743171	likely benign	Long QT syndrome 11	2016-12-13	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000170646	SCV000883381	benign	not provided	2017-09-29	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000853011	SCV000995767	likely benign	Catecholaminergic polymorphic ventricular tachycardia	2017-12-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001706104	SCV001821283	benign	not specified	2021-08-16	criteria provided, single submitter	clinical testing	Variant summary: AKAP9 c.510G>C (p.Glu170Asp) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0019 in 251328 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 574 fold of the estimated maximal expected allele frequency for a pathogenic variant in AKAP9 causing Long QT Syndrome phenotype (3.3e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.510G>C in individuals affected with Long QT Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign/benign, n=6). Based on the evidence outlined above, the variant was classified as benign.
CeGaT Center for Human Genetics Tuebingen	RCV000170646	SCV004164281	benign	not provided	2022-07-01	criteria provided, single submitter	clinical testing	AKAP9: BS1, BS2
Clinical Genetics, Academic Medical Center	RCV001706104	SCV001919073	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001706104	SCV001956421	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000170646	SCV001969969	likely benign	not provided		no assertion criteria provided	clinical testing