Submissions for variant NM_001148.6(ANK2):c.10118C>T (p.Ala3373Val)

gnomAD frequency: 0.00002  dbSNP: rs371358639

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000619754	SCV000738169	likely benign	Cardiovascular phenotype	2018-10-02	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.
CeGaT Center for Human Genetics Tuebingen	RCV000762106	SCV000892364	uncertain significance	not provided	2018-04-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001148598	SCV001309504	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	RCV001247601	SCV001421033	uncertain significance	Long QT syndrome	2022-02-04	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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 519510). This variant has not been reported in the literature in individuals affected with ANK2-related conditions. This variant is present in population databases (rs371358639, gnomAD 0.007%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 3373 of the ANK2 protein (p.Ala3373Val).
GeneDx	RCV000762106	SCV001803838	uncertain significance	not provided	2019-08-29	criteria provided, single submitter	clinical testing	Reported in one individual with hypertrophic cardiomyopathy in published literature (Lopes et al., 2015), although further details regarding a possible arrhythmia phenotype and segregation studies were not described; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID# 519510; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25351510)