Submissions for variant NM_000891.3(KCNJ2):c.1091A>G (p.Lys364Arg)

dbSNP: rs1060500054

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000464347	SCV000541390	uncertain significance	Andersen Tawil syndrome; Short QT syndrome type 3	2016-10-29	criteria provided, single submitter	clinical testing	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, but these predictions have not been confirmed by published functional studies. In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a KCNJ2-related disease. This sequence change replaces lysine with arginine at codon 364 of the KCNJ2 protein (p.Lys364Arg). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and arginine.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786146	SCV000924819	uncertain significance	not provided	2017-01-17	no assertion criteria provided	provider interpretation	p.Lys364Arg (c.1091A>G) in the KCNJ2 gene (NM_000891.2) Given lack of case data and inconsistent gene-phenotype information, yet absence in control populations, we consider this variant a variant of uncertain significance, probably benign and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has not been reported in any published cases of long QT syndrome (not including this patient's family). There are no entries in ClinVar for this variant. It appears to be novel. Variants in the KCNJ2 gene have been associated with long QT syndrome type 7, also known as Andersen syndrome. This is a syndromic condition characterized by ventricular arrhythmias, periodic paralysis, and distinct skeletal and facial dysmorphisms. Kidney and valvular heart problems have also been reported. It is inherited in an autosomal dominant manner. Given that our patient does not have any other clinical findings, it is unlikely that this variant is contributing to her prolonged QT interval. In silico analysis with PolyPhen-2 and SIFT predicts the variant to be tolerated. The Lysine at codon 364 is highly conserved across species. No other variants have been reported in association with disease at this codon or nearby codons. There is no variation at codon listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. The average coverage at that site in gnomAD is 90x.