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

gnomAD frequency: 0.00001  dbSNP: rs558502886

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV004589843	SCV000241415	uncertain significance	not provided	2024-05-08	criteria provided, single submitter	clinical testing	Reported in a patient with seizures and developmental deficits; however, another variant in a dominant gene was also observed (PMID: 28747464); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28747464, 34426522, 35370765, 36539902)
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
Labcorp Genetics (formerly Invitae), Labcorp	RCV000810914	SCV000951154	uncertain significance	EAST syndrome	2024-08-31	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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt KCNJ10 protein function with a negative predictive value of 80%. 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
Breakthrough Genomics, Breakthrough Genomics	RCV004589843	SCV005186996	uncertain significance	not provided		criteria provided, single submitter	not provided