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

Clinical significance:Conflicting interpretations of pathogenicity, Pathogenic(1);Uncertain significance(1) (Last evaluated: Apr 28, 2017)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000490297.3

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
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]

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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000267501Soonchunhyang University Bucheon Hospital,Soonchunhyang University Medical Centercriteria provided, single submitter
Uncertain significance
(Mar 18, 2016)
germlinereference population

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

SCV000915725Illumina Clinical Services Laboratory,Illuminacriteria provided, single submitter
Pathogenic
(Apr 28, 2017)
germlineclinical testing

PubMed (12)
[See all records that cite these PMIDs]

Citation Link,

SCV001462625Natera, Inc.no assertion criteria providedPathogenic
(Sep 16, 2020)
germlineclinical testing

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
East Asiangermlineunknown1not providednot providednot providednot providedreference population

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Functional confirmation of Gitelman's syndrome mutations in Japanese.

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

Hypertens Res. 2005 Oct;28(10):805-9.

PubMed [citation]
PMID:
16471174
See all PubMed Citations (13)

Details of each submission

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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1East Asian1not providednot providedreference population PubMed (2)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided1not providednot providednot provided

From Illumina Clinical Services Laboratory,Illumina, SCV000915725.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Natera, Inc., SCV001462625.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Aug 27, 2021

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