Submissions for variant NM_002241.5(KCNJ10):c.148C>T (p.Leu50Phe) (rs773510302)

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics	RCV000725019	SCV000333267	uncertain significance	not provided	2015-08-12	criteria provided, single submitter	clinical testing
GeneDx	RCV000725019	SCV000522187	uncertain significance	not provided	2016-12-23	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the KCNJ10 gene. The L50F variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The L50F variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a position that is conserved in mammals. However, the L50F variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae	RCV000646753	SCV000768538	uncertain significance	SeSAME syndrome	2018-02-10	criteria provided, single submitter	clinical testing	This sequence change replaces leucine with phenylalanine at codon 50 of the KCNJ10 protein (p.Leu50Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is present in population databases (rs773510302, ExAC 0.03%). This variant has not been reported in the literature in individuals with KCNJ10-related disease. ClinVar contains an entry for this variant (Variation ID: 282077). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.

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