Submissions for variant NM_004982.4(KCNJ8):c.263C>G (p.Ala88Gly)

gnomAD frequency: 0.00019  dbSNP: rs117808169

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000171006	SCV000223569	uncertain significance	not provided	2022-05-13	criteria provided, single submitter	clinical testing	Reported in a patient with atrioventricular nodal re-entrant tachycardia and concealed Brugada sign on ECG (Hasdemir et al., 2015); Identified independently and in conjunction with additional variants in individuals referred for cardiac genetic testing at GeneDx; segregation data are absent at this time; In silico analysis supports that this missense variant does not alter protein structure/function; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015); This variant is associated with the following publications: (PMID: 25998140)
Invitae	RCV000474015	SCV000550417	uncertain significance	Brugada syndrome	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 88 of the KCNJ8 protein (p.Ala88Gly). This variant is present in population databases (rs117808169, 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 KCNJ8-related conditions (PMID: 25998140, 28750076). ClinVar contains an entry for this variant (Variation ID: 190832). 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 KCNJ8 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002272156	SCV002557222	likely benign	Syndromic disease	2020-10-19	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as likely benign. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. Limited evidence for a gene-disease association, with few variants reported and with conflicting conclusions. (I) 0107 - This gene is associated with autosomal dominant disease. Limited evidence for a gene-disease association, with few variants reported. There is no disease associated with this gene in OMIM. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to glycine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2.1.1) <0.001 for a dominant condition. 0.000286 (81 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. Minor amino acid change, high conservation. (I) 0600 - Variant is located in the Inward rectifier potassium channel transmembrane domain (DECIPHER, RCSB PDB, NCBI_Conserved domains). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. ClinVar: VUSx2, LOVD3: Likely benign x1. PMID: 25998140: A patient with atrioventricular nodal re-entrant tachycardia (AVNT) and concealed Brugada syndrome. PMID: 28750076: A patient with HCM who also had a pathogenic variant in MYBPC3 and several other variants in other cardiac genes. At VCGS, in a patient who had a cardiac arrest and a diagnosis of LQTS. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting Pathogenic, (I) – Information, (SB) – Supporting Benign
Ambry Genetics	RCV002453585	SCV002739698	likely benign	Cardiovascular phenotype	2023-10-29	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.
Dept of Medical Biology, Uskudar University	RCV003318359	SCV004022053	uncertain significance	Long QT syndrome	2024-01-08	criteria provided, single submitter	research	Criteria: BS1, PP2