Submissions for variant NM_001148.6(ANK2):c.11119G>A (p.Asp3707Asn)

gnomAD frequency: 0.00013  dbSNP: rs199549660

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000170709	SCV000050642	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
GeneDx	RCV000170709	SCV000223262	uncertain significance	not provided	2020-02-03	criteria provided, single submitter	clinical testing	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: 27871843, 23861362, 30564305)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001082474	SCV000752878	likely benign	Long QT syndrome	2023-08-06	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852558	SCV000995258	uncertain significance	Supraventricular tachycardia	2017-10-02	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001144037	SCV001304611	likely benign	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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000185494	SCV001442714	benign	not specified	2020-10-26	criteria provided, single submitter	clinical testing	Variant summary: ANK2 c.11119G>A (p.Asp3707Asn) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00033 in 251152 control chromosomes, predominantly at a frequency of 0.0017 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 255 fold of the estimated maximal expected allele frequency for a pathogenic variant in ANK2 causing Long QT Syndrome phenotype (6.7e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One co-occurrence with another pathogenic variant has been internally reported (SCN5A c.5443_5446delTCTG, p.Ser1815ThrfsX18), providing supporting evidence for a benign role. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (2x) and likely benign (2x). Based on the evidence outlined above, the variant was classified as benign.
Ambry Genetics	RCV002426808	SCV002741474	likely benign	Cardiovascular phenotype	2020-02-24	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.
CeGaT Center for Human Genetics Tuebingen	RCV000170709	SCV003916912	benign	not provided	2023-03-01	criteria provided, single submitter	clinical testing	ANK2: BP4, BS1, BS2
Dept of Medical Biology, Uskudar University	RCV001082474	SCV004022067	uncertain significance	Long QT syndrome	2024-01-08	criteria provided, single submitter	research	Criteria: BS1, PP3
PreventionGenetics, part of Exact Sciences	RCV003954994	SCV004772086	likely benign	ANK2-related disorder	2023-02-01	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).