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	2024-12-23	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in individual(s) with neurodevelopmental disorders in published literature (PMID: 33004838); This variant is associated with the following publications: (PMID: 25650408, 33004838)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000200456	SCV000254720	uncertain significance	Long QT syndrome	2024-11-15	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1339 of the ANK2 protein (p.Pro1339Leu). This variant is present in population databases (rs371357815, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of ANK2-related conditions (PMID: 33004838). ClinVar contains an entry for this variant (Variation ID: 190570). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ANK2 protein function with a negative predictive value of 80%. 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.
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: 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.