Submissions for variant NM_002241.5(KCNJ10):c.296T>C (p.Leu99Pro)

dbSNP: rs540341763

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000354704	SCV000349848	uncertain significance	EAST syndrome	2018-01-12	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	RCV000259824	SCV000349849	uncertain significance	Autosomal recessive nonsyndromic hearing loss 4	2018-01-12	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.
GeneDx	RCV000520568	SCV000620084	uncertain significance	not provided	2017-08-17	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the KCNJ10 gene. The L99P variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The L99P variant is observed in 3/16284 (0.02%) alleles from individuals of South Asian background, including 1 homozygous individual (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The L99P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals. 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	RCV000354704	SCV002167301	uncertain significance	EAST syndrome	2023-05-15	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 293120). This variant has not been reported in the literature in individuals affected with KCNJ10-related conditions. This variant is present in population databases (rs540341763, gnomAD 0.02%), including at least one homozygous and/or hemizygous individual. This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 99 of the KCNJ10 protein (p.Leu99Pro).
Fulgent Genetics, Fulgent Genetics	RCV002487305	SCV002780919	uncertain significance	Autosomal recessive nonsyndromic hearing loss 4; Pendred syndrome; EAST syndrome	2022-05-07	criteria provided, single submitter	clinical testing