Submissions for variant NM_001148.6(ANK2):c.4456G>C (p.Val1486Leu)

gnomAD frequency: 0.00068  dbSNP: rs149678604

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000253621	SCV000318917	likely benign	Cardiovascular phenotype	2018-11-08	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.
GeneDx	RCV000437323	SCV000512040	uncertain significance	not provided	2021-12-17	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; 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 (ClinVar Variant ID# 263709; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 1830053, 18790697, 26109584)
Invitae	RCV000477573	SCV000545124	uncertain significance	Long QT syndrome	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1486 of the ANK2 protein (p.Val1486Leu). This variant is present in population databases (rs149678604, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with ANK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 263709). 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. 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.
Fulgent Genetics, Fulgent Genetics	RCV000764525	SCV000895608	uncertain significance	Cardiac arrhythmia, ankyrin-B-related	2018-10-31	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000437323	SCV000987637	uncertain significance	not provided		criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000764525	SCV004171336	uncertain significance	Cardiac arrhythmia, ankyrin-B-related		criteria provided, single submitter	clinical testing	The missense c.1606A>G (p.Asn536Asp) variant in ANK2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Val1486Leu variant is reported with an allele frequency of 0.01% in the gnomAD exomes database and is novel (not in any individuals) in 1000 Genomes database. This variant has been reported to the ClinVar database as Uncertain Significance. The amino acid Val at position 1486 is changed to a Leu changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as a Variant of Uncertain Significance (VUS).