NM_001126108.2(SLC12A3):c.2546T>A (p.Leu849His) AND Familial hypokalemia-hypomagnesemia

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Oct 2, 2021
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000490297.12

Allele description [Variation Report for NM_001126108.2(SLC12A3):c.2546T>A (p.Leu849His)]

NM_001126108.2(SLC12A3):c.2546T>A (p.Leu849His)

Gene:

SLC12A3:solute carrier family 12 member 3 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16q13

Genomic location:

Preferred name:

NM_001126108.2(SLC12A3):c.2546T>A (p.Leu849His)

HGVS:

NC_000016.10:g.56894555T>A
NG_009386.1:g.34349T>A
NM_000339.3:c.2573T>A
NM_001126107.2:c.2570T>A
NM_001126108.2:c.2546T>AMANE SELECT
NP_000330.3:p.Leu858His
NP_001119579.2:p.Leu857His
NP_001119580.2:p.Leu849His
NC_000016.9:g.56928467T>A
NM_000339.2:c.2573T>A
NM_001126108.2:c.2546T>A

Protein change:

L849H

Links:

dbSNP: rs185927948

NCBI 1000 Genomes Browser:

rs185927948

Molecular consequence:

NM_000339.3:c.2573T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126107.2:c.2570T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126108.2:c.2546T>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Familial hypokalemia-hypomagnesemia (GTLMNS)
Synonyms:: Potassium and magnesium depletion; Hypomagnesemia-hypokalemia, primary renotubular, with hypocalciuria
Identifiers:: MONDO: MONDO:0009904; MedGen: C0268450; Orphanet: 358; OMIM: 263800

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000915725	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Pathogenic (Apr 28, 2017)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 16471174, 15069170, 15198479, 10616841, 26041598, 12911530, 27173320, 23756661, 22802996, 21628937, 21757836, 17873326 Citation Link,
SCV001462625	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV002012228	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 2, 2021)	unknown	clinical testing	PubMed (4) [See all records that cite these PMIDs] 21628937, 26770037, 16471174, 25741868
SCV002055314	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 15, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	not provided	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
not provided	unknown	yes	1	not provided	not provided	1	not provided	clinical testing
East Asian	germline	unknown	1	not provided	not provided	not provided	not provided	reference population

Citations

PubMed

Four novel mutations in the thiazide-sensitive Na-Cl co-transporter gene in Japanese patients with Gitelman's syndrome.

Maki N, Komatsuda A, Wakui H, Ohtani H, Kigawa A, Aiba N, Hamai K, Motegi M, Yamaguchi A, Imai H, Sawada K.

Nephrol Dial Transplant. 2004 Jul;19(7):1761-6. Epub 2004 Apr 6.

PubMed [citation]

PMID:: 15069170

A high prevalence of Gitelman's syndrome mutations in Japanese.

Tago N, Kokubo Y, Inamoto N, Naraba H, Tomoike H, Iwai N.

Hypertens Res. 2004 May;27(5):327-31.

PubMed [citation]

PMID:: 15198479

See all PubMed Citations (14)

Details of each submission

From Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center, SCV000267501.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	East Asian	1	not provided	not provided	reference population	PubMed (2)

#	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		1	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV000915725.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (12)

Description

Across a selection of the available literature, the SLC12A3 c.2573T>A (p.Leu858His) variant, also known as c.2579T>A (p.Leu849His), has been reported in 10 studies and is found in a total of 13 patients with Gitelman syndrome, including two in a homozygous state, eight in a compound heterozygous state, and three in a heterozygous state where the second variant could not be identified (Monkawa et al. 2000; Fukuyama et al. 2003; Maki et al. 2004; Aoi et al. 2007; Tsutsui et al. 2011; Yagi et al. 2011; Imashuku et al. 2012; Ishimori et al. 2013; Miao et al. 2016; Mizokami et al. 2016). The p.Leu858His variant was absent from 400 control chromosomes in some studies (Monkawa et al. 2000; Fukuyama et al. 2003; Maki et al. 2004), however, the variant was detected in 47 out of 1852 healthy Japanese subjects in a heterozygous state (Tago et al. 2004) and is reported at a frequency of 0.01442 in the Japanese in Tokyo, Japan cohort of the 1000 Genomes Project. While this frequency is high, it is in alignment with the increased prevalence of Gitelman syndrome in Japan. In functional studies, sodium uptake of the p.Leu858His variant protein was found to be significantly reduced when expressed and evaluated in CHO cells, indicating that the p.Leu858His variant leads to loss of function (Naraba et al. 2005). Based on the evidence, the p.Leu858His variant is classified as pathogenic for Gitelman syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	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 Natera, Inc., SCV001462625.1

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

From 3billion, SCV002012228.1

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

Description

The variant has been reported to be in trans with a pathogenic variant as compound heterozygous in at least 2 similarly affected unrelated individuals (PMID: 21628937, 26770037, PM3_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 16471174, PS3) It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000597, PM2). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.783, PP3). Patient's phenotype is considered compatible with Gitelman syndrome (3billion dataset, PP4). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

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

From Genome-Nilou Lab, SCV002055314.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Flagged submissions

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000267501	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	flagged submission Reason: Outlier claim with insufficient supporting evidence Notes: None (ACMG Guidelines, 2015)	Uncertain significance (Mar 18, 2016)	germline	reference population	PubMed (2) [See all records that cite these PMIDs] 10616841, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000267501

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

flagged submission

Reason: Outlier claim with insufficient supporting evidence

Notes: None

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 18, 2016)

germline

reference population

PubMed (2)
[See all records that cite these PMIDs]

Last Updated: Sep 29, 2024

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