Submissions for variant NM_001148.6(ANK2):c.4016C>T (p.Pro1339Leu)

gnomAD frequency: 0.00007  dbSNP: rs371357815

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000170700	SCV000223253	uncertain significance	not provided	2021-02-08	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 190570; Landrum et al., 2016); 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: 25650408)
Invitae	RCV000200456	SCV000254720	uncertain significance	Long QT syndrome	2021-05-13	criteria provided, single submitter	clinical testing	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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with ANK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 190570). This variant is present in population databases (rs371357815, ExAC 0.01%). This sequence change replaces proline with leucine at codon 1339 of the ANK2 protein (p.Pro1339Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001260348	SCV001437285	likely benign	not specified	2020-09-08	criteria provided, single submitter	clinical testing	Variant summary: ANK2 c.4016C>T (p.Pro1339Leu) results in a non-conservative amino acid change located in the Ankyrin, UPA domain (IPR040745) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-05 in 251292 control chromosomes, predominantly at a frequency of 0.00018 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 27-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 Non-Finnish European origin. To our knowledge, no occurrence of c.4016C>T in individuals affected with Long QT Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics	RCV002354415	SCV002622214	likely benign	Cardiovascular phenotype	2021-11-29	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.