Submissions for variant NM_002241.5(KCNJ10):c.1061A>G (p.Lys354Arg) (rs142596580)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656852	SCV000241410	uncertain significance	not provided	2018-04-18	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the KCNJ10 gene. The K354R variant was reported in trans with another KCNJ10 variant (R271C) in an individual with Rett syndrome; however, no additional information was provided (Sajan et al., 2017). The K354R variant is observed in 61/126,624 (0.05%) alleles from individuals of European background in large population cohorts (Lek et al., 2016). The K354R variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics	RCV000656852	SCV000336762	uncertain significance	not provided	2015-11-16	criteria provided, single submitter	clinical testing
Invitae	RCV000463470	SCV000552195	uncertain significance	SeSAME syndrome	2018-05-26	criteria provided, single submitter	clinical testing	This sequence change replaces lysine with arginine at codon 354 of the KCNJ10 protein (p.Lys354Arg). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and arginine. This variant is present in population databases (rs142596580, ExAC 0.04%). This variant has been reported in an individual affected with Rett syndrome (PMID: 27171548). ClinVar contains an entry for this variant (Variation ID: 205824). 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 rare missense change that is not predicted to affect protein function, and is found in the population at an appreciable frequency. This variant is not anticipated to cause disease; however, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Athena Diagnostics Inc	RCV000656852	SCV000842577	uncertain significance	not provided	2018-06-04	criteria provided, single submitter	clinical testing