ClinVar Miner

Submissions for variant NM_002241.5(KCNJ10):c.1043G>A (p.Arg348His) (rs146396982)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000726871 SCV000241409 uncertain significance not provided 2018-12-06 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the KCNJ10 gene. The R348H variant has been published as a non-synonymous SNP in a patient with congenital hyperinsulinism of infancy (Proverbio et al., 2013). Additionally, the R348H variant has been reported previously in a patient with epileptic spasms, severe intellectual disability, autism spectrum disorder, and EEG abnormalities as well as in her father who has EEG abnormalities and a severe anxiety disorder (Sicca et al., 2016). Functional studies suggest that the R348H variant may affect channel function (Sicca et al., 2016). A different amino acid substitution at the same position (R348C) was reported in a patient with enlarged vestibular aqueduct syndrome who also had a single pathogenic variant in the SLC26A4 gene (Yang et al., 2009). Of note, the patient's unaffected mother and unaffected sibling also had the R348C variant in the KCNJ10 gene (Yang et al., 2009). The R348H variant is observed in 37/66,576 (0.06%) alleles from individuals of European background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R348H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000461889 SCV000552192 uncertain significance SeSAME syndrome 2018-11-02 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 348 of the KCNJ10 protein (p.Arg348His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs146396982, ExAC 0.06%). This variant has been reported in an individual with congenital hyperinsulinism of infancy (CHI) (PMID: 23869231). It has also been observed in an individual with epileptic spasm and her father without epilepsy (PMID: 27677466). ClinVar contains an entry for this variant (Variation ID: 205823). Experimental studies have shown that this missense change results in a gain-of-function channel function (PMID: 27677466). The current clinical and genetic evidence is not sufficient to establish whether gain-of-function variants in KCNJ10 cause disease. 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.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000726871 SCV000703750 uncertain significance not provided 2017-01-13 criteria provided, single submitter clinical testing
Ambry Genetics RCV000717237 SCV000848086 uncertain significance History of neurodevelopmental disorder 2016-10-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Fulgent Genetics,Fulgent Genetics RCV000764989 SCV000896168 uncertain significance Enlarged vestibular aqueduct; Pendred syndrome; SeSAME syndrome 2018-10-31 criteria provided, single submitter clinical testing

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