Submissions for variant NM_000891.3(KCNJ2):c.1169G>T (p.Ser390Ile)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002472086	SCV002768481	uncertain significance	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 VUS-3B. 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, PMID: 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 serine to isoleucine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated cytoplasmic domain (UniProt). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity. (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
Labcorp Genetics (formerly Invitae), Labcorp	RCV003775516	SCV004575159	uncertain significance	Andersen Tawil syndrome; Short QT syndrome type 3	2022-11-23	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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with KCNJ2-related conditions. This variant is present in population databases (rs748535146, gnomAD 0.0009%). This sequence change replaces serine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 390 of the KCNJ2 protein (p.Ser390Ile).