Submissions for variant NM_001148.6(ANK2):c.2060A>G (p.Asn687Ser)

gnomAD frequency: 0.00009  dbSNP: rs29372

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000171786	SCV000050797	benign	not specified	2013-06-24	criteria provided, single submitter	research
GeneDx	RCV001711458	SCV000223281	uncertain significance	not provided	2023-03-15	criteria provided, single submitter	clinical testing	Identified in a cohort of stillbirths undergoing sequencing for genes associated with arrhythmia; however, clinical information is not available (Munroe et al., 2018); 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: 25649125, 27527004, 16741161, 23861362, 17161064, 19862833, 29874177)
Invitae	RCV000700217	SCV000828965	uncertain significance	Long QT syndrome	2023-11-14	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 687 of the ANK2 protein (p.Asn687Ser). This variant is present in population databases (rs29372, gnomAD 0.01%). This missense change has been observed in individual(s) with unexplained stillbirth (PMID: 29874177). ClinVar contains an entry for this variant (Variation ID: 190594). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ANK2 protein function with a negative predictive value of 80%. 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	RCV002415721	SCV002725122	likely benign	Cardiovascular phenotype	2022-05-31	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000171786	SCV003844701	likely benign	not specified	2023-02-14	criteria provided, single submitter	clinical testing	Variant summary: ANK2 c.2060A>G (p.Asn687Ser) 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 4.6e-05 in 283602 control chromosomes (gnomAD). The observed variant frequency is approximately 7 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 benign. c.2060A>G has been reported in the literature in one individual affected with torsades de pointes and one stillbirth case (Mank-Seymour_2006, Munroe_2018). These reports do not provide unequivocal conclusions about association of the variant with Long QT Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite this variant as uncertain significance (n=3) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000477910	SCV000536759	uncertain significance	Cardiac arrhythmia, ankyrin-B-related	2015-12-10	no assertion criteria provided	research