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

gnomAD frequency: 0.00023  dbSNP: rs34591340

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000058355	SCV000223208	uncertain significance	not provided	2023-06-28	criteria provided, single submitter	clinical testing	Reported in association with LQTS, HCM, and early onset atrial fibrillation; no case-specific clinical or segregation data were provided in these publications (Mullally et al., 2013; Lopes et al., 2015; Goodyer et al., 2019); Identified in one individual of Mexican American ancestry from a control cohort of 190 anonymized individuals; variant reported as p.(G1406C) due to alternate nomenclature (Mohler et al., 2007); Functional studies in mouse neonatal cardiomyocytes suggest this variant may not impact ankyrin-B function; the clinical validity of these studies remains to be established (Mohler et al., 2007); 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: 23631430, 25351510, 23174487, 28988457, 22581653, 31638414, 17242276)
Ambry Genetics	RCV000247414	SCV000320304	likely benign	Cardiovascular phenotype	2018-11-27	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	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	2024-01-04	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
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000987467	SCV002769530	uncertain significance	Cardiac arrhythmia, ankyrin-B-related	2022-09-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as VUS-3C. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (OMIM, PMID:12571597, PMID:15178757, PMID:17242276.) (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0112 - Variants in this gene are known to have reduced penetrance. Limited evidence (PMID:26230511). (N) 0200 - Variant is predicted to result in a missense amino acid change from glycine to cysteine (exon 35). (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition: 0.0002795 (79 het, 0 hom). (P) 0309 An alternative amino acid change at the same position has been observed in gnomAD p.(Gly1439Asp): 0.000004 (1 het, 0 hom). (N) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. Major change. High conservation. (N) 0600 - Variant is located in an annotated domain or motif. UPA domain (NCBI_Conserved Domains, (N) 0704 - Comparable variant has low previous evidence for pathogenicity. NM_ 001148.4(ANK2):c.4315G>A; Gly1439Ser: considered Likely pathogenic in 1 patient with atrial fibrillation (PMID: 30276209). (P) 0808 - Previous reports of pathogenicity are conflicting. ClinVar: 5x VUS, 2x Likely benign, 1x benign, 1 not provided, with most recent submissions and evaluations tending towards benign/ likely benign. LOVD3: Likely benign x1 (VKGL Data sharing initiative, Netherlands). Earlier publications indicate an association with LQTS (PMID: 23174487, PMID: 28988457). However, more recent reports suggest is a VUS, with not enough evidence, or a VUS, likely benign (PMID: 28589536, PMID: 31638414, respectively. (N) 0905 - No segregation evidence has been identified for this variant. (N) 1004 - Moderate functional evidence supporting normal protein function. PMID:17242276: Referred to as G4216T, G1406C, due to a different transcript used. Effects were similar to wildtype, and rescued abnormal phenotype (contraction rate and spatial patterns of Ca2+ release in ankyrin-B heterozygous and homozygous knockout mice. (B) 1206 - Variant is paternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000987467	SCV003920059	uncertain significance	Cardiac arrhythmia, ankyrin-B-related	2021-03-30	criteria provided, single submitter	clinical testing	ANK2 NM_001148.4 exon 35 p.Gly1439Cys (c.4315G>T): This variant has been reported in the literature in at least 1 individual with HCM (Lopes 2015 PMID:25351510) as well as at least 2 individuals with a clinical suspicion of Long QT syndrome (Lieve 2013 PMID:23631430, Mullally 2013 PMID:23174487). This variant is present in 64/126500 European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs34591340). This variant is present in ClinVar (Variation ID:67606). Evolutionary conservation and computational predictive tools for this variant are unclear. Functional studies involving cardiomyocytes suggest that this variant may not impact the protein and displays properties similar to wild-type (Mohler 2007 PMID:17242276). Further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
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.