NM_001126108.2(SLC12A3):c.1388G>A (p.Gly463Glu) AND not provided

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jan 8, 2024
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001980278.3

Allele description [Variation Report for NM_001126108.2(SLC12A3):c.1388G>A (p.Gly463Glu)]

NM_001126108.2(SLC12A3):c.1388G>A (p.Gly463Glu)

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.1388G>A (p.Gly463Glu)

HGVS:

NC_000016.10:g.56879594G>A
NG_009386.2:g.19388G>A
NM_000339.3:c.1388G>A
NM_001126107.2:c.1385G>A
NM_001126108.2:c.1388G>AMANE SELECT
NP_000330.3:p.Gly463Glu
NP_001119579.2:p.Gly462Glu
NP_001119580.2:p.Gly463Glu
NC_000016.9:g.56913506G>A
NG_009386.1:g.19388G>A
NM_000339.2:c.1388G>A

Protein change:

G462E

Links:

dbSNP: rs1375515522

NCBI 1000 Genomes Browser:

rs1375515522

Molecular consequence:

NM_000339.3:c.1388G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126107.2:c.1385G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126108.2:c.1388G>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
SCV002271087	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jan 8, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 12112667, 27582097, 31672324, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002271087

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jan 8, 2024)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Identification of fifteen novel mutations in the SLC12A3 gene encoding the Na-Cl Co-transporter in Italian patients with Gitelman syndrome.

Syrén ML, Tedeschi S, Cesareo L, Bellantuono R, Colussi G, Procaccio M, Alì A, Domenici R, Malberti F, Sprocati M, Sacco M, Miglietti N, Edefonti A, Sereni F, Casari G, Coviello DA, Bettinelli A.

Hum Mutat. 2002 Jul;20(1):78. Erratum in: Hum Mutat. 2002 Oct;20(4):321.

PubMed [citation]

PMID:: 12112667

Functionomics of NCC mutations in Gitelman syndrome using a novel mammalian cell-based activity assay.

Valdez-Flores MA, Vargas-Poussou R, Verkaart S, Tutakhel OA, Valdez-Ortiz A, Blanchard A, Treard C, Hoenderop JG, Bindels RJ, Jeleń S.

Am J Physiol Renal Physiol. 2016 Dec 1;311(6):F1159-F1167. doi: 10.1152/ajprenal.00124.2016. Epub 2016 Aug 31.

PubMed [citation]

PMID:: 27582097

See all PubMed Citations (4)

Details of each submission

From Invitae, SCV002271087.3

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

Description

This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 463 of the SLC12A3 protein (p.Gly463Glu). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with SLC12A3-related conditions (PMID: 12112667). ClinVar contains an entry for this variant (Variation ID: 1488711). 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%. This variant disrupts the p.Gly463 amino acid residue in SLC12A3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27582097, 31672324). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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

Last Updated: Jun 23, 2024

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