Submissions for variant NM_001148.6(ANK2):c.11231C>A (p.Thr3744Asn)

gnomAD frequency: 0.00077  dbSNP: rs121912705

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV001841248	SCV000050753	likely benign	Cardiac arrhythmia	2013-06-24	criteria provided, single submitter	research
GeneDx	RCV000723633	SCV000223265	likely benign	not provided	2021-05-13	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 16253912, 23631430, 15178757, 31539150, 32164423, 23861362)
Eurofins Ntd Llc (ga)	RCV000723633	SCV000230577	uncertain significance	not provided	2017-08-10	criteria provided, single submitter	clinical testing
Invitae	RCV000204635	SCV000260737	likely benign	Long QT syndrome	2024-01-03	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000204635	SCV000263782	uncertain significance	Long QT syndrome	2015-02-25	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000618056	SCV000737813	likely benign	Cardiovascular phenotype	2023-03-03	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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000723633	SCV000987420	likely benign	not provided		criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000723633	SCV001154264	benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	ANK2: BS1, BS2
Illumina Laboratory Services, Illumina	RCV000019674	SCV001304614	uncertain significance	Cardiac arrhythmia, ankyrin-B-related	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000223796	SCV002041623	likely benign	not specified	2021-11-07	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000723633	SCV002049155	likely benign	not provided	2020-12-08	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000019674	SCV003920126	uncertain significance	Cardiac arrhythmia, ankyrin-B-related	2021-03-30	criteria provided, single submitter	clinical testing	ANK2 NM_001148.4 exon 42 p.Thr3744Asn (c.11231C>A): This variant has been reported in the literature in at least 4 individuals with clinical suspicion of arrhythmia (Mohler 2004 PMID:15178757, Lieve 2013 PMID:23631430). However, this variant is present in 0.1% (157/126452) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs121912705). This variant is present in ClinVar, with conflicting classifications of this variant (Variation ID:18057). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant suggests that this variant does not cause disease, but requires further evidence. Therefore, the clinical significance of this variant is uncertain.
OMIM	RCV000019674	SCV000039972	pathogenic	Cardiac arrhythmia, ankyrin-B-related	2004-06-15	no assertion criteria provided	literature only
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV001841248	SCV000089867	not provided	Cardiac arrhythmia		no assertion provided	literature only	This variant has been reported as associated with Cardiac arrhythmia in the following publications (PMID:15178757). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000223796	SCV000280047	uncertain significance	not specified	2015-10-12	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. We classify this variant as a variant of unknown significance. This variant has been previously reported in two unrelated individuals with borderline prolonged QT intervals (Mohler P et at., 2004; due to alternative nomenclature, they report it as Thr1626Asn). One of the reported individuals had a daughter, also heterozygous for the variant, who died suddenly at age 19 with no prior cardiac symptoms. All other carriers of the variant in the two families were asymptomatic. This is a conservative amino acid change, resulting in the replacement of a threonine (polar) with an asparagine (polar). Threonine at this location is conserved across most mammalian species for which data is available with the exception of the mouse and x-tropicalis. In silico analysis with PolyPhen-2 predicts the variant to be “possibly damaging” with a score of 0.951. In total, the variant has been seen in at least 12/6700 individuals from published controls and publicly available population datasets. This variant is listed in the NHLBI Exome Sequencing Project dataset, where it was found in 11 of 6503 genotyped individuals (2 of 2203 African Americans and 9 of 4300 European Americans), indicating that it may be a rare benign variant. Another variant affecting the same residue, T3744P, was also seen in 1 of 6503 genotyped individuals. This variant, T3744N, has been listed in dpSNP, but has not been documented in 1000 genomes. It was observed in 1 of 200 published control individuals of African American descent (Sherman J et al., 2005).