Submissions for variant NM_001148.6(ANK2):c.56G>A (p.Ser19Asn)

gnomAD frequency: 0.00001  dbSNP: rs369260005

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000315698	SCV000447140	uncertain significance	Cardiac arrhythmia, ankyrin-B-related	2018-01-12	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001342296	SCV001536218	uncertain significance	Long QT syndrome	2021-07-31	criteria provided, single submitter	clinical testing	This variant is present in population databases (rs369260005, ExAC 0.003%). This sequence change replaces serine with asparagine at codon 19 of the ANK2 protein (p.Ser19Asn). The serine residue is weakly conserved and there is a small physicochemical difference between serine and asparagine. This variant has not been reported in the literature in individuals with ANK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 347301). 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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain.
GeneDx	RCV001584061	SCV001812408	likely benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002348100	SCV002650095	uncertain significance	Cardiovascular phenotype	2023-04-20	criteria provided, single submitter	clinical testing	The c.56G>A (p.S19N) alteration is located in exon 1 (coding exon 1) of the ANK2 gene. This alteration results from a G to A substitution at nucleotide position 56, causing the serine (S) at amino acid position 19 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.