Submissions for variant NM_000891.3(KCNJ2):c.119G>A (p.Arg40Gln)

gnomAD frequency: 0.00004  dbSNP: rs766143485

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000406881	SCV000405988	uncertain significance	Short QT syndrome type 3	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000308982	SCV000405989	uncertain significance	Andersen Tawil syndrome	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000347359	SCV000405990	uncertain significance	Atrial fibrillation, familial, 9	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV000489623	SCV000577559	uncertain significance	not provided	2018-11-29	criteria provided, single submitter	clinical testing	The R40Q variant of uncertain significance in the KCNJ2 gene has been reported as a likely benign variant in one patient with primary electrical disease who also harbors a loss of function variant in the PKP2 gene (Proost et al., 2017). This variant is observed in 6/277196 (0.002%) alleles from individuals of multiple ethnic backgrounds in large population cohorts (Lek et al., 2016). The R40Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Finally, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000795350	SCV000934806	uncertain significance	Andersen Tawil syndrome; Short QT syndrome type 3	2025-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 40 of the KCNJ2 protein (p.Arg40Gln). This variant is present in population databases (rs766143485, gnomAD 0.008%). This missense change has been observed in individual(s) with primary electrical disease (PED), however this individual also had a pathogenic variant in another PED-related gene (PMID: 28341588, 29874177). ClinVar contains an entry for this variant (Variation ID: 324830). 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 KCNJ2 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects KCNJ2 function (PMID: 29874177). 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.
Robert's Program, Boston Children's Hospital	RCV001788198	SCV002030082	uncertain significance	SUDDEN INFANT DEATH SYNDROME	2021-10-01	criteria provided, single submitter	research	We classify this variant as a variant of uncertain significance using ACMG/AMP criteria. As this variant has functional evidence supporting pathogenicty, we suspect this variant is favoring pathogenic.
Ambry Genetics	RCV002348069	SCV002646855	benign	Cardiovascular phenotype	2023-11-22	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	RCV002487428	SCV002787969	uncertain significance	Andersen Tawil syndrome; Short QT syndrome type 3; Atrial fibrillation, familial, 9	2021-08-31	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000489623	SCV003799755	uncertain significance	not provided	2022-03-08	criteria provided, single submitter	clinical testing	The KCNJ2 c.119G>A; p.Arg40Gln variant (rs766143485) is reported in the literature in an individual affected with fetal thrombotic vasculopathy (Munroe 2018), and an individual affected with primary electrical disease who also carried a pathogenic PKP2 variant (Proost 2017). This variant is also reported in ClinVar (Variation ID: 324830), but is only observed on five alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 40 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.201). In vitro functional analyses demonstrate reduced channel function (Munroe 2018). However, given the limited clinical and functional data, the significance of this variant is uncertain at this time. References: Munroe PB et al. Postmortem Genetic Testing for Cardiac Ion Channelopathies in Stillbirths. Circ Genom Precis Med. 2018 Jan;11(1):e001817. PMID: 29874177. Proost D et al. Targeted Next-Generation Sequencing of 51 Genes Involved in Primary Electrical Disease. J Mol Diagn. 2017 May;19(3):445-459. PMID: 28341588.