Submissions for variant NM_000891.3(KCNJ2):c.208G>T (p.Ala70Ser)

gnomAD frequency: 0.00005  dbSNP: rs375605948

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000459178	SCV000541392	uncertain significance	Andersen Tawil syndrome; Short QT syndrome type 3	2023-12-04	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 70 of the KCNJ2 protein (p.Ala70Ser). This variant is present in population databases (rs375605948, gnomAD 0.009%). This missense change has been observed in individual(s) with clinical features of long QT syndrome (PMID: 30847666). ClinVar contains an entry for this variant (Variation ID: 403977). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt KCNJ2 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV001508993	SCV001715463	uncertain significance	not provided	2020-06-24	criteria provided, single submitter	clinical testing
GeneDx	RCV001508993	SCV001812648	uncertain significance	not provided	2021-01-22	criteria provided, single submitter	clinical testing	Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 403977; Landrum et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Reported in association with LQTS; additional patient-specific data were not provided (van Lint et al., 2019); This variant is associated with the following publications: (PMID: 30847666)
Ambry Genetics	RCV002418347	SCV002726597	benign	Cardiovascular phenotype	2023-09-29	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Fulgent Genetics, Fulgent Genetics	RCV002488997	SCV002778507	uncertain significance	Andersen Tawil syndrome; Short QT syndrome type 3; Atrial fibrillation, familial, 9	2021-08-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003479121	SCV004223024	likely benign	not specified	2023-11-21	criteria provided, single submitter	clinical testing	Variant summary: KCNJ2 c.208G>T (p.Ala70Ser) results in a conservative amino acid change located in the Potassium channel, inwardly rectifying, transmembrane domain (IPR040445) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 251482 control chromosomes (gnomAD). The observed variant frequency is approximately 4.77 fold of the estimated maximal expected allele frequency for a pathogenic variant in KCNJ2 causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is benign. c.208G>T has been reported in the literature in an individual affected with long QT syndrome (van Lint_2019). This report does not provide unequivocal conclusions about association of the variant with Arrhythmia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 30847666). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.