Submissions for variant NM_001148.6(ANK2):c.7105G>T (p.Val2369Phe)

gnomAD frequency: 0.00004  dbSNP: rs758054052

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000230793	SCV000286256	uncertain significance	Long QT syndrome	2023-03-07	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: 238587). This variant has not been reported in the literature in individuals affected with ANK2-related conditions. This variant is present in population databases (rs758054052, gnomAD 0.01%). This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 2369 of the ANK2 protein (p.Val2369Phe).
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV000853461	SCV000996372	uncertain significance	Primary dilated cardiomyopathy	2017-06-20	criteria provided, single submitter	research	The ANK2 Val2369 variant has been reported previously in 1 Long QT (Invitae, ClinVar: SCV000286256.1) and 1 HCM patient (Lopes, et al., 2015). We identified this variant in a DCM proband that was diagnosed after suffering a cardiac arrest. The probands sibling passed away from cardiomyopathy and another family died suddenly however segregation was not possible. The variant is present in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/) at an allele frequency > 0.00004, which is greater then expected for the disease. In silico models, SIFT, MutationTaster and PolyPhen-2 predict the change to be benign. In summary, the variant is present in the general population at a frequency higher then expected for the disease and in silico tools predict this variant to be benign, therefore we classify ANK2 Val2369Phe as a variant of 'uncertain significance'.
GeneDx	RCV001785525	SCV002028069	uncertain significance	not provided	2021-11-12	criteria provided, single submitter	clinical testing	Identified in patients with HCM in the published literature (Lopes et al., 2015); In silico analysis supports that this missense variant does not alter protein structure/function; 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); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 238587; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 25351510)
Ambry Genetics	RCV002365186	SCV002662628	likely benign	Cardiovascular phenotype	2024-02-27	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.
Fulgent Genetics, Fulgent Genetics	RCV002478848	SCV002792935	uncertain significance	Cardiac arrhythmia, ankyrin-B-related	2022-01-08	criteria provided, single submitter	clinical testing