ClinVar Miner

Submissions for variant NM_001148.6(ANK2):c.9526G>T (p.Asp3176Tyr) (rs138928206)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000230181 SCV000286270 uncertain significance Long QT syndrome 2020-08-31 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with tyrosine at codon 3176 of the ANK2 protein (p.Asp3176Tyr). The aspartic acid residue is weakly conserved and there is a large physicochemical difference between aspartic acid and tyrosine. This variant is present in population databases (rs138928206, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in individual(s) with Brugada syndrome or sudden unexplained death in infancy (PMID: 25650408, 26350513). ClinVar contains an entry for this variant (Variation ID: 234981). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C0). 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 RCV000246497 SCV000319070 likely benign Cardiovascular phenotype 2020-07-23 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
Illumina Clinical Services Laboratory,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 2017-07-14 criteria provided, single submitter clinical testing The D3176Y variant of uncertain significance in the ANK2 gene has been 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 variants in other genes associated with arrhythmia, and no clinical information or segregation data was provided. This variant is observed in 21/66560 (0.03%) alleles from individuals of European (Non-Finnish) ancestry in the Exome Aggregation Consortium (ExAC) dataset (Lek et al., 2016; Exome Variant Server). The D3176Y variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Nevertheless, this substitution occurs at a position that is not conserved across species and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
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.

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