Submissions for variant NM_000890.5(KCNJ5):c.430A>G (p.Ile144Val)

gnomAD frequency: 0.00002  dbSNP: rs369703183

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000357625	SCV000368929	uncertain significance	Familial hyperaldosteronism type III	2018-01-13	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	RCV000267619	SCV000368930	likely benign	Congenital long QT syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Invitae	RCV001062268	SCV001227055	uncertain significance	Long QT syndrome	2023-07-31	criteria provided, single submitter	clinical testing	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. 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 KCNJ5 protein function. ClinVar contains an entry for this variant (Variation ID: 303628). This variant has not been reported in the literature in individuals affected with KCNJ5-related conditions. This variant is present in population databases (rs369703183, gnomAD 0.01%). This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 144 of the KCNJ5 protein (p.Ile144Val).
Ambry Genetics	RCV002328803	SCV002627571	likely benign	Cardiovascular phenotype	2022-06-03	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470842	SCV002767745	uncertain significance	Long QT syndrome 13	2020-10-19	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as 3C-VUS. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. The link between variants in KCNJ5 and LQTS is disputed. (I) 0107 - This gene is associated with autosomal dominant disease. Variants in this gene are associated with autosomal dominant familial hyperaldosteronism type III (MIM #613677). (I) 0200 - Variant is predicted to result in a missense amino acid change from isoleucine to valine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (9 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated helical domain in the pore region (NCBI). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has one VUS entry in ClinVar related to familial hyperaldosteronism, and one likely benign and one VUS entry related to 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
Revvity Omics, Revvity	RCV003133217	SCV003814028	uncertain significance	not provided	2021-02-11	criteria provided, single submitter	clinical testing