Submissions for variant NM_153766.3(KCNJ1):c.601C>T (p.Leu201Phe)

gnomAD frequency: 0.00004  dbSNP: rs200320892

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV001092303	SCV001248736	pathogenic	not provided	2021-10-01	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001251500	SCV001427117	pathogenic	Bartter disease type 2	2022-06-24	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Bartter syndrome, type 2 (MIM#241200). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from leucine to phenylalanine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (87 heterozygote(s), 1 homozygote). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated IRK potassium channel domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported several times as pathogenic, and observed in homozygous and compound heterozygous individuals with Bartter syndrome (ClinVar, PMID: 29942493, PMID: 24659592, PMID: 32997650, PMID: 24400161). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Xenopus oocytes demonstrating impaired channel activity resulting in the reduction of potassium currents (PMID: 24400161). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Labcorp Genetics (formerly Invitae), Labcorp	RCV001092303	SCV002242769	pathogenic	not provided	2024-01-18	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 220 of the KCNJ1 protein (p.Leu220Phe). This variant is present in population databases (rs200320892, gnomAD 0.2%). This missense change has been observed in individuals with Bartter syndrome (PMID: 9502574, 10611379, 24400161, 24659592, 24696311, 29942493). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 872043). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects KCNJ1 function (PMID: 10611379, 12911542, 24400161). For these reasons, this variant has been classified as Pathogenic.
3billion	RCV001251500	SCV002521404	pathogenic	Bartter disease type 2	2022-05-22	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.036%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.69; 3Cnet: 0.07). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000872043). A different missense change at the same codon (p.Leu201Arg) has been reported to be associated with KCNJ1 related disorder (ClinVar ID: VCV000870375 / PMID: 32573669). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282455	SCV002572306	pathogenic	Bartter syndrome	2024-08-02	criteria provided, single submitter	clinical testing	Variant summary: KCNJ1 c.658C>T (p.Leu220Phe) results in a non-conservative amino acid change located in the C-terminal domain (IPR041647) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00036 in 249254 control chromosomes, predominantly at a frequency of 0.0024 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 2-fold of the estimated maximal expected allele frequency for a pathogenic variant in KCNJ1 causing Bartter Syndrome, Type 2 phenotype (0.0011), suggesting that the variant might be a benign polymorphism. However, the variant c.658C>T, has also been reported in the literature in compound heterozygous and homozygous state, in individuals (mostly of South Asian or Middle Eastern origin) who were affected with Bartter Syndrome, Type 2, where homozygotes were described to have a milder, adult onset phenotype (e.g. Vollmer_1998, Kunzelmann_2000, Srivastava_2013, Sharma_2014, Huang_2014, Jayasinghe_2021, Elfert_2020). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and while an early in vitro study demonstrated no major functional impact (Kunzelmann_2000), a later study described a partial loss of function when the L220F variant was expressed alone (i.e. mimicking a homozygous state), while it almost completely abolished channel activity when co-expressed together with another variant (S219R, i.e. mimicking a compound heterozygous state), in addition, the variant also affected phosphatidylinositol 4,5-bisphosphate (PIP2)-dependent gating of the channel (Srivastava_2013). ClinVar contains an entry for this variant (Variation ID: 872043). Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV001251500	SCV002811629	likely pathogenic	Bartter disease type 2	2022-05-07	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001251500	SCV003820863	pathogenic	Bartter disease type 2	2023-10-26	criteria provided, single submitter	clinical testing
GeneDx	RCV001092303	SCV003840615	uncertain significance	not provided	2023-03-01	criteria provided, single submitter	clinical testing	Published functional studies suggest a damaging effect (Peters et al., 2003; Srivastava et al., 2013); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24696311, 10878442, 12911542, 10611379, 34426522, 32997650, 24400161, 9502574, 32939031, 24659592, 35195872, 29942493)
Intergen, Intergen Genetics and Rare Diseases Diagnosis Center	RCV001251500	SCV004041601	pathogenic	Bartter disease type 2	2023-10-10	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	RCV001251500	SCV004099282	pathogenic	Bartter disease type 2	2023-10-28	criteria provided, single submitter	clinical testing	This heterozygous mis-sense variant is identified in a 5 year malewith polyurea, hypokalemia, GDD, dandy walker malformation, nephrocalcinosis and optic disc hypoplasia. This nucleotide change is present in gnomAD database with a low allele frequency 0.0357% [PM2]. Insilico prediction [REVEL=0.71] predicts deleterious nature of this variant [PP3]. The variant is identified in trans [PM3] with another variant p.Thr191Pro. A clinvar entry for this variant is available. This variant is submitted to clinvar database [Variation ID: 7116] with “Conflicting interpretation of pathogenecity”, [Pathogenic (7), Likely Pathogenic (1), Uncertain Significance (1)” by multiple submitters [PP5]. Based on the clinical correlation and available evidence, this variant is classified as "Pathogenic".
Neuberg Centre For Genomic Medicine, NCGM	RCV001251500	SCV004171899	pathogenic	Bartter disease type 2	2023-05-20	criteria provided, single submitter	clinical testing	The missense variant c.601C>T(p.Leu201Phe) in KCNJ1 gene has been reported in homozygous and compound heterozygous state in multiple individuals with Bartter syndrome (Elfert et. al., 2020; Walsh et. al., 2018; Srivastava et. al., 2013). It has also been observed to segregate with disease in related individuals. Experimental studies have shown that this missense change affects KCNJ1 function (Srivastava et. al., 2013). The observed variant has allele frequency of 0.03% in gnomAD exomes database. This variant has been submitted to the ClinVar database as Uncertain Significance / Likely Pathogenic / Pathogenic (multiple submitters). The amino acid change p.Leu201Phe in KCNJ1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Multiple lines of computational evidence (Polyphen - probably damaging , SIFT - tolerated and MutationTaster - disease causing) predicts conflicting evidence on protein structure and function for this variant. The amino acid Leu at position 201 is changed to a Phe changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. In the absence of another reportable variant in KCNJ1 gene, the molecular diagnosis is not confirmed.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV001251500	SCV004808196	uncertain significance	Bartter disease type 2	2024-03-29	criteria provided, single submitter	clinical testing