ClinVar Miner

Submissions for variant NM_001148.6(ANK2):c.1937C>T (p.Ser646Phe)

dbSNP: rs786205724
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000170682 SCV000223235 pathogenic not provided 2024-04-26 criteria provided, single submitter clinical testing Published functional studies demonstrate variant results in reduced ankyrin-B expression in rat cardiomyoblasts and abnormal localization in mice cardiomyocytes, and adversely affects targeting of downstream binding partners, thus supporting a loss-of-function effect (PMID: 28196901); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28765088, 29163198, 31477143, 29661707, 30415094, 28196901)
PreventionGenetics, part of Exact Sciences RCV003398876 SCV004112630 uncertain significance ANK2-related disorder 2023-06-27 criteria provided, single submitter clinical testing The ANK2 c.1937C>T variant is predicted to result in the amino acid substitution p.Ser646Phe. This variant has been reported in two families of Gitxsan ancestry with Ankyrin-B syndrome (ABS), long QT syndrome, and structural heart disease, with functional in vitro studies demonstrating this variant disrupted normal localization to the plasma membrane in mouse myocytes (Swayne et al. 2017. PubMed ID: 28196901). Another study showed no significant functional effect of this variant on Cav2.1 levels in HEK293T cells (Choi et al. 2019. PubMed ID: 31477143). The designation of ANK2 as a self-sufficient long QT syndrome susceptibility gene has been questioned due to the high frequency of putative ABS-causative variants in public exomes and the nature of the ABS cardiac phenotype (Giudicessi et al. 2018. PubMed ID: 29661707). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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