Submissions for variant NM_153766.3(KCNJ1):c.505C>T (p.Arg169Cys)

gnomAD frequency: 0.00078  dbSNP: rs138120505

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	RCV000490394	SCV000267373	uncertain significance	Bartter disease type 2	2016-03-18	criteria provided, single submitter	reference population
Athena Diagnostics	RCV000517253	SCV000613857	likely benign	not specified	2016-12-14	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001853388	SCV002299056	uncertain significance	not provided	2022-09-07	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 188 of the KCNJ1 protein (p.Arg188Cys). This variant is present in population databases (rs138120505, gnomAD 0.3%). This missense change has been observed in individual(s) with clinical features of Bartter syndrome (PMID: 19096086). ClinVar contains an entry for this variant (Variation ID: 225398). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The cysteine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000517253	SCV002500676	likely benign	not specified	2022-03-28	criteria provided, single submitter	clinical testing	Variant summary: KCNJ1 c.562C>T (p.Arg188Cys) results in a non-conservative amino acid change in 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 0.00024 in 249916 control chromosomes, predominantly at a frequency of 0.003 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2.7 fold of the estimated maximal expected allele frequency for a pathogenic variant in KCNJ1 causing Bartter Syndrome, Type 2 phenotype (0.0011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.562C>T has been reported in the literature as a heterozygous non-informative (second allele not specified) genotype in at-least one individual of Congolese ethnic origin (African subcontinent) reportedly affected with neonatal Bartter Syndrome, Type 2 (example, Brochard_2009). These report(s) do not provide unequivocal conclusions about association of the variant with Bartter Syndrome, Type 2. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely benign and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics	RCV002515597	SCV003712784	likely benign	Inborn genetic diseases	2022-02-25	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.