Submissions for variant NM_000891.3(KCNJ2):c.224C>T (p.Thr75Met)

dbSNP: rs104894585

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000170993	SCV000223556	pathogenic	not provided	2023-06-23	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect (results in a dominant-negative effect and reduces channel function) (Davies et al., 2005; Eckhardt et al., 2007); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17582433, 17341397, 23867365, 24861851, 22581653, 16217063, 30847666, 35460302)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000644783	SCV000766497	pathogenic	Andersen Tawil syndrome; Short QT syndrome type 3	2024-08-28	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 75 of the KCNJ2 protein (p.Thr75Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of KCNJ2-related conditions (PMID: 15911703, 16217063, 17341397, 17582433, 18452873, 24861851). ClinVar contains an entry for this variant (Variation ID: 67565). 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 80%. Experimental studies have shown that this missense change affects KCNJ2 function (PMID: 16217063, 17341397, 17582433). This variant disrupts the p.Thr75 amino acid residue in KCNJ2. Other variant(s) that disrupt this residue have been observed in individuals with KCNJ2-related conditions (PMID: 12796536, 15276028, 15911703), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV004629147	SCV005124723	likely pathogenic	Cardiovascular phenotype	2024-05-02	criteria provided, single submitter	clinical testing	The p.T75M variant (also known as c.224C>T), located in coding exon 1 of the KCNJ2 gene, results from a C to T substitution at nucleotide position 224. The threonine at codon 75 is replaced by methionine, an amino acid with similar properties. This alteration has been reported in subjects with features of Andersen-Tawil syndrome (Zhang L et al. Circulation, 2005 May;111:2720-6; Tani Y et al. J Mol Cell Cardiol, 2007 Aug;43:187-96; Villar-Quiles RN et al. Eur J Neurol, 2022 Aug;29:2398-2411; Johnson JN et al. Heart Rhythm, 2008 May;5:704-9). This alteration also demonstartes an impact on protein function (Davies NP et al. Neurology, 2005 Oct;65:1083-9; Tani Y et al. J Mol Cell Cardiol, 2007 Aug;43:187-96). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058302	SCV000089822	not provided	Congenital long QT syndrome		no assertion provided	literature only	This variant has been reported in the following publications (PMID:16217063;PMID:17582433).