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

Germline classification:: Pathogenic (7 submissions)
Last evaluated:: Jan 16, 2026
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:: RCV000490297.22

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

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]

Condition(s)

Name:: Familial hypokalemia-hypomagnesemia (GTLMNS)
Synonyms:: HYPOMAGNESEMIA-HYPOKALEMIA, PRIMARY RENOTUBULAR, WITH HYPOCALCIURIA; POTASSIUM AND MAGNESIUM DEPLETION; gitelman syndrome
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.	criteria provided, single submitter (Natera Variant Classification Schema (03/2026))	Pathogenic (Sep 16, 2025)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 21757836, 19508680 Citation Link,
SCV002012228	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 16, 2026)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 26770037, 10616841, 21628937, 16471174, 22009145, 15069170, 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]
SCV005418075	Juno Genomics, Hangzhou Juno Genomics, Inc	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005640177	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 14, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

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	yes	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
East Asian	germline	unknown	1	not provided	not provided	not provided	not provided	reference population

Citations

PubMed

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

Graves' disease and Gitelman syndrome.

Mizokami T, Hishinuma A, Kogai T, Hamada K, Maruta T, Higashi K, Tajiri J.

Clin Endocrinol (Oxf). 2016 Jan;84(1):149-50. doi: 10.1111/cen.12829. Epub 2015 Jul 3. No abstract available.

PubMed [citation]

PMID:: 26041598

See all PubMed Citations (16)

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., SCV001462625.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The c.2573T>A variant in SLC12A3 is a missense variant predicted to cause substitution of leucine to histidine at amino acid 858. This variant is rare in the general population with a frequency below the threshold expected for the associated phenotype(s). This variant has been observed in one or more individuals affected with the associated recessive disease, as either homozygous or compound heterozygous with a second variant (PMID: 21757836, 19508680). Computational prediction algorithms indicate this variant is likely to affect gene or protein function. Given the available evidence, this variant is 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 3billion, SCV002012228.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

The variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (total allele frequency: 0.019%). Predicted Consequence/Location: Missense variant Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 16471174). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.78 (>=0.6, sensitivity 0.68 and specificity 0.92)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000225470 /PMID: 10616841 /3billion dataset). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 15069170, 21628937, 26770037). The variant has been reported to co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated families (PMID: 15069170). Different missense changes at the same codon (p.Leu849Phe, p.Leu849Pro) have been reported to be associated with SLC12A3-related disorder (ClinVar ID: VCV002736354 /PMID: 22009145, 37702302). 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	germline	yes	not provided	not provided	not provided		not provided	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

From Juno Genomics, Hangzhou Juno Genomics, Inc, SCV005418075.2

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

Description

Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;For recessive disorders, detected in trans with a pathogenic variant.;Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.;Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc).

#	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

From Fulgent Genetics, Fulgent Genetics, SCV005640177.1

#	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	unknown	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: Jun 27, 2026

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