Submissions for variant NM_000891.3(KCNJ2):c.430G>A (p.Gly144Ser)

gnomAD frequency: 0.00001  dbSNP: rs199473378

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001382882	SCV001581837	pathogenic	Andersen Tawil syndrome; Short QT syndrome type 3	2024-12-22	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 144 of the KCNJ2 protein (p.Gly144Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Andersen-Tawil syndrome (PMID: 11371347). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 67573). 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 expected to disrupt KCNJ2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KCNJ2 function (PMID: 12163457, 12909315, 14522976, 22002906). This variant disrupts the p.Gly144 amino acid residue in KCNJ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15911703, 16541386, 30516834). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470749	SCV002769146	pathogenic	Andersen Tawil syndrome	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0104 - Dominant negative is a known mechanism of disease in this gene and is associated with Andersen syndrome (MIM#170390) (OMIM, PMID: 22589293, 22186697). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (GeneReviews). (I) 0115 - Variants in this gene are known to have variable expressivity. Some individuals carrying Andersen-Tawil syndrome variants lack the triad of clinical features (PMID: 22589293). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to serine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (1 heterozygote, 0 homozygote). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated inward rectifier potassium channel transmembrane domain (DECIPHER). (I) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. p.(Gly144Asp) and p.(Gly144Ala) have been seen in several unrelated individuals with Andersen syndrome (ClinVar, PMID:12909315, 22589293, 33057326). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has previously been seen in four individuals with Andersen syndrome (ClinVar, PMID: 11371347, 12163457, 17221872). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function.Patch clamp assays using oocytes with site directed mutagenesis show this variant stops the protein from being able to form homomultimeric channels and causes disease in a dominant negative manner (PMID: 12163457, 12909315). However, patch clamp assays have been shown to be unreliable, therefore results from these studies are used with caution during variant classification. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058311	SCV000089831	not provided	Congenital long QT syndrome		no assertion provided	literature only	This variant has been reported in the following publications (PMID:11371347;PMID:12163457;PMID:15028050;PMID:17221872;PMID:22002906).