ClinVar Miner

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

gnomAD frequency: 0.00034  dbSNP: rs146396982
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Total submissions: 12
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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 EAST syndrome 2022-10-25 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 348 of the KCNJ10 protein (p.Arg348His). This variant is present in population databases (rs146396982, gnomAD 0.07%). This missense change has been observed in individual(s) with clinical features of KCNJ10-related conditions (PMID: 27677466). ClinVar contains an entry for this variant (Variation ID: 205823). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt KCNJ10 protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on KCNJ10 function (PMID: 27677466). 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.
Eurofins Ntd Llc (ga) RCV000726871 SCV000703750 uncertain significance not provided 2017-01-13 criteria provided, single submitter clinical testing
Ambry Genetics RCV002314724 SCV000848086 uncertain significance Inborn genetic diseases 2019-05-10 criteria provided, single submitter clinical testing The p.R348H variant (also known as c.1043G>A), located in coding exon 1 of the KCNJ10 gene, results from a G to A substitution at nucleotide position 1043. The arginine at codon 348 is replaced by histidine, an amino acid with highly similar properties. In one study, this variant was reported in an individual with congenital hyperinsulinism of infancy (Proverbio MC et al. PLoS ONE, 2013 Jul;8:e68740). It was also detected in a child with epileptic spasms, intellectual disability, and autism as well as in her father who had severe anxiety disorder and focal abnormalities on EEG (Sicca F et al. Sci Rep, 2016 Sep;6:34325). In a child with infantile spasms, developmental delay, an abnormal EEG, left frontal lobe cortical dysplasia, hypotonia, and brachycephaly, this variant co-occurred with an apparently de novo SCN8A pathogenic mutation (Butler KM et al. Epilepsy Res., 2017 01;129:17-25). Of note, none of the four aforementioned individuals were found to carry a second KCNJ10 alteration. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on available evidence to date, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics RCV000764989 SCV000896168 uncertain significance Autosomal recessive nonsyndromic hearing loss 4; Pendred syndrome; EAST syndrome 2018-10-31 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000461889 SCV001255844 uncertain significance EAST syndrome 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina RCV001099391 SCV001255845 uncertain significance Autosomal recessive nonsyndromic hearing loss 4 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Genetic Services Laboratory, University of Chicago RCV001818453 SCV002066105 uncertain significance not specified 2020-03-09 criteria provided, single submitter clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV003224208 SCV003920098 uncertain significance Autosomal recessive nonsyndromic hearing loss 4; EAST syndrome 2021-03-30 criteria provided, single submitter clinical testing KCNJ10 NM_002241.4 exon 2 p.Arg348His (c.1043G>A): This variant has been reported in the literature in 1 individual with congenital hyperinsulinism of infancy (CHI) (Proverbio 2013 PMID:23869231), as well as in 1 individual with autism and epilepsy, segregating with disease in 1 affected relative (Sicca 2016 PMID:7677466). This variant is present in 83/126554 European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs146396982). This variant is present in ClinVar (Variation ID:205823). Evolutionary conservation and computational predictive tools for this variant are unclear. Zebrafish and patch-clamp functional studies suggest a deleterious effect of this variant; however, further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille RCV001252025 SCV001427772 uncertain significance Intellectual disability 2019-01-01 no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000726871 SCV001955541 uncertain significance not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000726871 SCV001968636 uncertain significance not provided no assertion criteria provided clinical testing

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