Submissions for variant NM_000891.3(KCNJ2):c.935G>A (p.Arg312His)

dbSNP: rs786205820

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000170994	SCV000223557	pathogenic	not provided	2017-12-28	criteria provided, single submitter	clinical testing	The R312H pathogenic variant in the KCNJ2 gene has been reported in association with Andersen-Tawil syndrome (Sacconi et al., 2009; Delannoy et al., 2013). Sacconi et al., reported one individual with features of Andersen syndrome, including periodic paralysis prompted by hypokalemia in the context of exercise or stress and mild dysmorphic facial features. Additionally, Sacconi et al., determined the R312H variant resulted in a loss of ion channel function by in vitro studies.R312H results in a conservative amino acid substitution of Arginine at a position that is conserved across species. A missense variant in the same residue (R312C) and missense variants in nearby residues (M307I, M307V, T309I, N318S) have been reported in HGMD in association with Andersen-Tawil syndrome (Stenson et al., 2014), further supporting the functional importance of this region of the protein. Furthermore, the R312H pathogenic variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.
Invitae	RCV000644779	SCV000766493	pathogenic	Andersen Tawil syndrome; Short QT syndrome type 3	2022-02-02	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg312 amino acid residue in KCNJ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12796536, 15911703, 22806368, 25284084). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 expected to disrupt KCNJ2 protein function. ClinVar contains an entry for this variant (Variation ID: 190820). This missense change has been observed in individuals with clinical features of Andersen-Tawil syndrome (PMID: 19570891, 23867365). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 312 of the KCNJ2 protein (p.Arg312His).
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	RCV002054023	SCV002320707	likely pathogenic	Andersen Tawil syndrome	2021-10-27	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002054023	SCV002557685	pathogenic	Andersen Tawil syndrome	2022-06-24	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: 0103 - Dominant negative, loss of function and gain of function are known mechanisms of disease in this gene. Dominant negative is associated with Andersen-Tawil Syndrome (ATS) (MIM#170390), while loss of function variants are proposed to lead to atypical ATS with isolated cardiac phenotype. Gain of function is associated with short QT syndrome 3 (MIM#609622) (GeneReviews, PMID: 24383070). (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 (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2: 1 heterozygote, 0 homozygotes). (I) 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 C-terminal domain (DECIPHER). (I) 0703 - Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. p.(Arg312Cys) has been identified in individuals with Andersen-Tawil Syndrome (MIM#170390) (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in at least five individuals with Andersen-Tawil Syndrome (MIM#170390) (ClinVar; PMID: 19570891, 23867365, 28606196). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Patch clamp studies done on patient’s cultured myoblasts demonstrated a reduction in steady state current (PMID: 19570891). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences	RCV002054023	SCV002600035	pathogenic	Andersen Tawil syndrome	2022-04-12	no assertion criteria provided	research