ClinVar Miner

Submissions for variant NM_001148.6(ANK2):c.8843C>G (p.Ala2948Gly) (rs138438183)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000423348 SCV000516718 uncertain significance not provided 2019-01-11 criteria provided, single submitter clinical testing The A2948G variant of uncertain significance in the ANK2 gene has been reported in two sisters with Brugada syndrome (Allegue et al., 2015). This variant has also been observed both independently and in conjunction with additional cardiogenetic variants, in other unrelated individuals referred for arrhythmia genetic testing at GeneDx; however, segregation data are not available. A2948G is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Finally, the A2948G variant has been observed in 50/126,176 (0.04%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016).Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Invitae RCV000463576 SCV000545145 uncertain significance Long QT syndrome 2020-10-27 criteria provided, single submitter clinical testing This sequence change replaces alanine with glycine at codon 2948 of the ANK2 protein (p.Ala2948Gly). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and glycine. This variant is present in population databases (rs138438183, ExAC 0.03%). This variant has been reported in two related individuals affected with Brugada syndrome (PMID: 26230511). ClinVar contains an entry for this variant (Variation ID: 379553). 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. 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.
Ambry Genetics RCV000620461 SCV000737637 likely benign Cardiovascular phenotype 2018-04-19 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
Fulgent Genetics,Fulgent Genetics RCV000764527 SCV000895610 uncertain significance Cardiac arrhythmia, ankyrin B-related 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000764527 SCV001311064 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.

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