Submissions for variant NM_001148.6(ANK2):c.7183A>C (p.Thr2395Pro)

gnomAD frequency: 0.00017  dbSNP: rs201693280

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000537225	SCV000627663	uncertain significance	Long QT syndrome	2024-01-13	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 2395 of the ANK2 protein (p.Thr2395Pro). This variant is present in population databases (rs201693280, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of ANK2-related conditions (PMID: 23396983, 24981977, 26220970, 28255936). ClinVar contains an entry for this variant (Variation ID: 457049). 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 disruptive. 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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV001256865	SCV001433357	uncertain significance	Conduction disorder of the heart	2019-06-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001264520	SCV001442715	likely benign	not specified	2020-10-26	criteria provided, single submitter	clinical testing	Variant summary: ANK2 c.7183A>C (p.Thr2395Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 250596 control chromosomes, predominantly at a frequency of 0.00046 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 69 fold of the estimated maximal expected allele frequency for a pathogenic variant in ANK2 causing Long QT Syndrome phenotype (6.7e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.7183A>C has been reported in the literature in individuals affected with Long QT Syndrome, hypertrophic cardiomyopathy and adult-onset sudden cardiac death (Lopes_2013, Brion_2014, Campuzano_2017). These reports do not provide unequivocal conclusions about association of the variant with Long QT Syndrome. One co-occurrence with another pathogenic variant has been internally reported (SCN5A c.5443_5446delTCTG, p.Ser1815ThrfsX18), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (3x). Based on the evidence outlined above, the variant was classified as likely benign.
GeneDx	RCV000786103	SCV001771942	uncertain significance	not provided	2020-07-01	criteria provided, single submitter	clinical testing	Observed in patients with LQTS and SCD in the published literature (Brion et al., 2014; Campuzano et al., 2017); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 457049; Landrum et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26220970, 28255936, 28988457, 24981977)
Ambry Genetics	RCV002377012	SCV002667138	likely benign	Cardiovascular phenotype	2022-06-08	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.
Revvity Omics, Revvity	RCV000786103	SCV003818594	uncertain significance	not provided	2019-03-11	criteria provided, single submitter	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786103	SCV000924747	uncertain significance	not provided	2017-03-17	no assertion criteria provided	provider interpretation