Submissions for variant NM_001148.6(ANK2):c.5758G>A (p.Gly1920Arg)

gnomAD frequency: 0.00004  dbSNP: rs140189724

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000617415	SCV000738136	likely benign	Cardiovascular phenotype	2021-06-24	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.
Invitae	RCV001055077	SCV001219442	uncertain significance	Long QT syndrome	2023-05-31	criteria provided, single submitter	clinical testing	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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 519494). This missense change has been observed in individual(s) with clinical features of Brugada syndrome (PMID: 26230511). This variant is present in population databases (rs140189724, gnomAD 0.01%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1920 of the ANK2 protein (p.Gly1920Arg).
Illumina Laboratory Services, Illumina	RCV001149833	SCV001310829	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	RCV001264521	SCV001442716	likely benign	not specified	2020-10-26	criteria provided, single submitter	clinical testing	Variant summary: ANK2 c.5758G>A (p.Gly1920Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-05 in 250626 control chromosomes, predominantly at a frequency of 0.00016 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 24 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 Non-Finnish European origin. c.5758G>A has been reported in the literature in individuals affected with Brugada Syndrome (Allegue_2015, Campuzano_2019). 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. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
GeneDx	RCV003233762	SCV003930845	uncertain significance	not provided	2023-06-12	criteria provided, single submitter	clinical testing	Identified in one individual with Brugada syndrome in published literature (Allegue et al., 2015); Located in exon 38, which is reported as being expressed in a brain-specific transcript (Otto et al, 1991; Cunha et al, 2008; Wu et al, 2015); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26109584, 18790697, 1830053, 30821013, 26230511)
Dept of Medical Biology, Uskudar University	RCV001055077	SCV004021969	uncertain significance	Long QT syndrome	2024-01-08	criteria provided, single submitter	research	Criteria: BP4