ClinVar Miner

Submissions for variant NM_001148.6(ANK2):c.4315G>T (p.Gly1439Cys) (rs34591340)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000058355 SCV000223208 uncertain significance not provided 2018-08-29 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the ANK2 gene. The G1439C variant has been previously published in at least one individual in association with LQTS (Mullally et al., 2013), and has been observed in other individuals referred for LQTS genetic testing at GeneDx. However, no segregation data are available for the published case, or the cases observed at GeneDx, to further clarify the role of this variant in disease. This variant, denoted as G1406C due to the use of alternate nomenclature, was also identified in one individual from a control cohort of 190 anonymized individuals, however, due to anonymization, this individual's clinical history was not known (Mohler et al., 2007). Additionally, the G1439C variant has been reported in one individual with HCM (Lopes et al., 2015), although further details regarding a personal or family history of arrhythmia were not described. The G1439C variant has also been observed in 33/66702 (0.05%) alleles from individuals of Non-Finnish European ancestry in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Furthermore, the G1439C variant is classified as a likely benign variant in ClinVar by a different clinical laboratory (SCV000320304.1; Landrum et al., 2016).Nevertheless, the G1439C 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. Although cysteine (C) is the wild-type residue at this position in one non-mammalian species, this substitution occurs at a position that is conserved in mammals, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, a study of GFP-tagged ankyrin-B protein in mouse neonatal cardiomyocytes revealed that ankyrin-B harboring G1439C demonstrated normal protein expression and targeting and displayed properties similar to wild-type, including rescuing abnormal ankyrin-B+/- and ankyrin-B-/- phenotypes (Mohler et al., 2007). While these studies by Mohler et al. (2007) suggest this variant may not impact ankyrin-B function, the clinical validity of these studies remains to be established.
Ambry Genetics RCV000247414 SCV000320304 likely benign Cardiovascular phenotype 2018-11-27 criteria provided, single submitter clinical testing Other data supporting benign classification
Illumina Clinical Services Laboratory,Illumina RCV000987467 SCV000447178 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.
Invitae RCV000363942 SCV000627648 likely benign Long QT syndrome 2020-11-05 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000363942 SCV000740499 uncertain significance Long QT syndrome 2017-06-28 criteria provided, single submitter clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000852554 SCV000995254 uncertain significance Cardiomyopathy; Hypertrophic cardiomyopathy 2019-03-18 criteria provided, single submitter clinical testing
Mendelics RCV000987467 SCV001136762 benign Cardiac arrhythmia, ankyrin B-related 2019-05-28 criteria provided, single submitter clinical testing
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058355 SCV000089875 not provided not provided no assertion provided literature only This variant has been reported in the following publications (PMID:17242276).
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000058355 SCV000924742 uncertain significance not provided 2017-04-21 no assertion criteria provided provider interpretation p.Gly1439Cys (c.4315G>T), was identified in exon 35 ANK2 (NM_001148.4) Given the weak case data and its prevalence in the general population, we consider this variant a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least 2 unrelated cases of Long QT syndrome (not including this patient's family). The case data is weak. This variant is present in ClinVar. It is interpreted as likely benign by GeneDx and Ambry genetics. It is interpreted as a variant of uncertain significance by Illumina Clinical Services. It has also been submitted by Royal Brompton, but they did not provide a classification. This variant was seen in 1 out of 855 unrelated patients referred for Long QT testing (Vieve et al 2013). The researchers classified it as a VUS/likely benign. Clinical information on this individual, including their QTc interval, is available for review. It is important to note that this patient is likely the same as a patient present in ClinVar, submitted by GeneDx. It was also present in 1 out of 403 individuals with Long QT syndrome (Mullally et al 2013). The glycine at codon 1439 is moderately conserved across species, as are neighboring amino acids. Nearby codons have been classified as likely benign or there are conflicting interpretations of pathogenicity. The variant was reported online in 71 of 122,869 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, Ashkenazi, Latino descent. Specifically, the variant was observed in 57 of 55,746 individuals of European descent (MAF=0.017%), 6 of 16,779 individuals of Latino descent, 4 of 11,150 individuals of Finnish descent, 2 of 7,651 individuals of African descent and 2 of 2,738 individuals of "other" descent. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease.

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