NM_153766.3(KCNJ1):c.601C>T (p.Leu201Phe) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Jan 18, 2024
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001092303.25

Allele description [Variation Report for NM_153766.3(KCNJ1):c.601C>T (p.Leu201Phe)]

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

Gene:

KCNJ1:potassium inwardly rectifying channel subfamily J member 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11q24.3

Genomic location:

Preferred name:

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

HGVS:

NC_000011.10:g.128839643G>A
NG_009379.1:g.32731C>T
NM_000220.6:c.658C>T
NM_153764.3:c.601C>T
NM_153765.3:c.652C>T
NM_153766.3:c.601C>TMANE SELECT
NM_153767.4:c.601C>T
NP_000211.1:p.Leu220Phe
NP_722448.1:p.Leu201Phe
NP_722449.3:p.Leu218Phe
NP_722450.1:p.Leu201Phe
NP_722451.1:p.Leu201Phe
NC_000011.9:g.128709538G>A
NC_000011.9:g.128709538G>A
NM_000220.4:c.658C>T
NM_000220.5:c.658C>T
NM_000220.6:c.658C>T
NM_153766.2:c.601C>T

Protein change:

L201F

Links:

dbSNP: rs200320892

NCBI 1000 Genomes Browser:

rs200320892

Molecular consequence:

NM_000220.6:c.658C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_153764.3:c.601C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_153765.3:c.652C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_153766.3:c.601C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_153767.4:c.601C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001248736	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Oct 1, 2021)	germline	clinical testing	Citation Link,
SCV002242769	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 18, 2024)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 9502574, 24659592, 24696311, 29942493, 10611379, 12911542, 24400161, 28492532
SCV003840615	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Mar 1, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001248736

CeGaT Center for Human Genetics Tuebingen

criteria provided, single submitter

(CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)

Pathogenic
(Oct 1, 2021)

germline

clinical testing

Citation Link,

SCV002242769

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 18, 2024)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

SCV003840615

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Mar 1, 2023)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	4	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Two novel mutations of the gene for Kir 1.1 (ROMK) in neonatal Bartter syndrome.

Vollmer M, Koehrer M, Topaloglu R, Strahm B, Omran H, Hildebrandt F.

Pediatr Nephrol. 1998 Jan;12(1):69-71.

PubMed [citation]

PMID:: 9502574

Nephrocalcinosis as adult presentation of Bartter syndrome type II.

Huang L, Luiken GP, van Riemsdijk IC, Petrij F, Zandbergen AA, Dees A.

Neth J Med. 2014 Feb;72(2):91-3.

PubMed [citation]

PMID:: 24659592

See all PubMed Citations (8)

Details of each submission

From CeGaT Center for Human Genetics Tuebingen, SCV001248736.21

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	4	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		4	not provided	not provided	not provided

From Invitae, SCV002242769.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneDx, SCV003840615.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 12, 2024

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