NM_001126108.2(SLC12A3):c.2546T>A (p.Leu849His) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Dec 14, 2023
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:: RCV000713330.12

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]

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
SCV000843927	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (Apr 1, 2016)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 17873326, 16471174, 10616841, 21757836, 21628937, 19489442, 12911530, 15069170, 15198479, 26467025
SCV000940176	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 14, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 15069170, 21628937, 21757836, 26041598, 26770037, 16471174, 28492532
SCV002520209	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Nov 18, 2021)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000843927

Athena Diagnostics

criteria provided, single submitter

(Athena Diagnostics Criteria)

Pathogenic
(Apr 1, 2016)

germline

clinical testing

PubMed (10)
[See all records that cite these PMIDs]

SCV000940176

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 14, 2023)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV002520209

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Nov 18, 2021)

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	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

Citations

PubMed

Two novel genotypes of the thiazide-sensitive Na-Cl cotransporter (SLC12A3) gene in patients with Gitelman's syndrome.

Aoi N, Nakayama T, Tahira Y, Haketa A, Yabuki M, Sekiyama T, Nakane C, Mano H, Kawachi H, Sato N, Soma M, Matsumoto K.

Endocrine. 2007 Apr;31(2):149-53.

PubMed [citation]

PMID:: 17873326

Novel mutations in thiazide-sensitive Na-Cl cotransporter gene of patients with Gitelman's syndrome.

Monkawa T, Kurihara I, Kobayashi K, Hayashi M, Saruta T.

J Am Soc Nephrol. 2000 Jan;11(1):65-70. doi: 10.1681/ASN.V11165.

PubMed [citation]

PMID:: 10616841

See all PubMed Citations (13)

Details of each submission

From Athena Diagnostics, SCV000843927.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000940176.6

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

Description

This sequence change replaces leucine, which is neutral and non-polar, with histidine, which is basic and polar, at codon 858 of the SLC12A3 protein (p.Leu858His). This variant is present in population databases (rs185927948, gnomAD 0.09%). This missense change has been observed in individual(s) with SLC12A3-related conditions (PMID: 15069170, 21628937, 21757836, 26041598, 26770037). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as p.Leu849His. ClinVar contains an entry for this variant (Variation ID: 225470). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SLC12A3 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SLC12A3 function (PMID: 16471174). 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, SCV002520209.2

#	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 demonstrate a damaging effect as p.(L858H) results in loss-of-function (Naraba et al., 2005); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17873326, 33163079, 27173320, 26770037, 22802996, 23756661, 10616841, 15198479, 15069170, 21757836, 19489442, 31105122, 33328404, 21628937, 26041598, 33348466, 32884933, 30596175, 16471174)

#	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: Sep 29, 2024

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