Submissions for variant NM_002241.5(KCNJ10):c.652C>T (p.Leu218Phe)

gnomAD frequency: 0.00001  dbSNP: rs558502886

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000187817	SCV000241415	uncertain significance	not specified	2016-09-19	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the KCNJ10 gene. The L218F variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The L218F variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project and was not observed with any significant frequency in the 1000 Genomes Project. The L218F variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably 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.
Fulgent Genetics, Fulgent Genetics	RCV000764990	SCV000896169	uncertain significance	Autosomal recessive nonsyndromic hearing loss 4; Pendred syndrome; EAST syndrome	2022-02-06	criteria provided, single submitter	clinical testing
Invitae	RCV000810914	SCV000951154	uncertain significance	EAST syndrome	2022-08-22	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 218 of the KCNJ10 protein (p.Leu218Phe). This variant is present in population databases (rs558502886, gnomAD 0.009%). This missense change has been observed in individual(s) with severe epilepsy and profound developmental delay (PMID: 28747464). ClinVar contains an entry for this variant (Variation ID: 205829). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects KCNJ10 function (PMID: 28747464). 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.
Illumina Laboratory Services, Illumina	RCV000810914	SCV001257982	uncertain significance	EAST syndrome	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001101379	SCV001257983	uncertain significance	Autosomal recessive nonsyndromic hearing loss 4	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000810914	SCV001984231	uncertain significance	EAST syndrome	2020-09-24	criteria provided, single submitter	clinical testing