Submissions for variant NM_004982.4(KCNJ8):c.332A>G (p.Glu111Gly)

gnomAD frequency: 0.00018  dbSNP: rs138391404

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001896671	SCV002173057	uncertain significance	Brugada syndrome	2023-12-27	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 111 of the KCNJ8 protein (p.Glu111Gly). This variant is present in population databases (rs138391404, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with KCNJ8-related conditions. ClinVar contains an entry for this variant (Variation ID: 1400429). 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 95%. 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	RCV002272525	SCV002557666	likely benign	Hypertrichotic osteochondrodysplasia Cantu type	2023-07-16	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely benign. Following criteria are met: 0101 - Gain of function is the proposed mechanism of disease in this gene and is associated with Cantú syndrome (MIM#239850) (PMID: 24700710). (I) 0107 - This gene is associated with autosomal dominant disease (PMIDs: 24176758, 24700710, 32215968). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to glycine. (I) 0251 - This variant is heterozygous. (I) 0308 - Population frequency for this variant is out of keeping with known incidence of Cantú syndrome (MIM#239850) (gnomAD v2: 19 heterozygotes, 0 homozygotes). (SB) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (p.(Glu111Gln): 2 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated inward rectifier potassium channel transmembrane domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been classified once as a VUS by one clinical diagnostic laboratory (ClinVar). (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	RCV002324296	SCV002609057	benign	Cardiovascular phenotype	2024-01-18	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.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003228016	SCV003924118	uncertain significance	not provided	2021-03-30	criteria provided, single submitter	clinical testing	KCNJ8 NM_004982.3 exon 2 p.Glu111Gly (c.332A>G): This variant has not been reported in the literature and is present in 0.01% (15/126698) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/12-21926219-T-C). Evolutionary conservation is unclear; computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Mayo Clinic Laboratories, Mayo Clinic	RCV003228016	SCV004226312	uncertain significance	not provided	2023-04-27	criteria provided, single submitter	clinical testing	BP4
PreventionGenetics, part of Exact Sciences	RCV003913439	SCV004730078	uncertain significance	KCNJ8-related disorder	2024-02-05	no assertion criteria provided	clinical testing	The KCNJ8 c.332A>G variant is predicted to result in the amino acid substitution p.Glu111Gly. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.