Submissions for variant NM_001148.6(ANK2):c.9526G>T (p.Asp3176Tyr)

gnomAD frequency: 0.00018  dbSNP: rs138928206

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000230181	SCV000286270	benign	Long QT syndrome	2023-11-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000246497	SCV000319070	likely benign	Cardiovascular phenotype	2020-07-23	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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	RCV000625127	SCV000447216	uncertain significance	Cardiac arrhythmia, ankyrin-B-related	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV000767141	SCV000522181	uncertain significance	not provided	2022-12-28	criteria provided, single submitter	clinical testing	Identified in one individual with Brugada syndrome (Le Scouarnec et al., 2015), and in one individual with sudden unexplained death (SUD) at two months old (Hertz et al., 2016); however, both individuals also harbored additional variants in other genes associated with arrhythmia; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26350513, 26159999, 25650408)
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000625127	SCV000743827	likely benign	Cardiac arrhythmia, ankyrin-B-related	2017-07-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000223719	SCV001361446	likely benign	not specified	2019-11-05	criteria provided, single submitter	clinical testing	Variant summary: ANK2 c.9526G>T (p.Asp3176Tyr) results in a non-conservative amino acid change located in the Ankyrin repeat-containing domain (IPR020683) of 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 0.00017 in 251078 control chromosomes, predominantly at a frequency of 0.00034 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 34 fold of the estimated maximal expected allele frequency for a pathogenic variant in ANK2 causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.9526G>T has been reported in the literature in an individual affected with Brugada syndrome and in an infant with sudden unexplained death in infancy (SUDI). In both of these cases, other possibly pathogenic causal variants have been identified (SCN5A c.2254G>A, p.Gly752Arg, LeScouarnec_2015; TRPM4 c.1575G>A, p.W525*, Hertz_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=3) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000223719	SCV000280052	uncertain significance	not specified	2013-04-26	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. Based on the data reviewed below we consider it a variant of uncertain significance. It has not previously been reported in association with disease. The p.D3176Y variant (also known as c.9526 G>T) is located in coding exon 38 of the ANK2 gene. The aspartic acid at codon 3176 is replaced by tyrosine, an amino acid with highly dissimilar properties. This variant was previously reported in dbSNP as rs138928206. Based on data from the NHLBI Exome Sequencing Project (ESP), the T-allele has an overall frequency of approximately 0.04% (5/13006), having been observed in 0.06% (5/8600) of European American alleles, and not reported in 4406 African American alleles studied. This variant was not reported in population-based cohorts in the 1000 Genomes Project. Based on protein sequence alignment, this amino acid position is not well conserved in available vertebrate species. This alteration is predicted to be benign by Polyphen, yet deleterious by SIFT in silico analyses. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Clinical Genetics, Academic Medical Center	RCV000767141	SCV001924553	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000767141	SCV001952494	likely benign	not provided		no assertion criteria provided	clinical testing