NM_001126108.2(SLC12A3):c.2864G>C (p.Arg955Pro) AND not provided

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Nov 6, 2022
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:: RCV003679658.1

Allele description [Variation Report for NM_001126108.2(SLC12A3):c.2864G>C (p.Arg955Pro)]

NM_001126108.2(SLC12A3):c.2864G>C (p.Arg955Pro)

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.2864G>C (p.Arg955Pro)

HGVS:

NC_000016.10:g.56904402G>C
NG_009386.2:g.44196G>C
NG_139603.1:g.434G>C
NM_000339.3:c.2891G>C
NM_001126107.2:c.2888G>C
NM_001126108.2:c.2864G>CMANE SELECT
NM_001410896.1:c.2861G>C
NP_000330.3:p.Arg964Pro
NP_001119579.2:p.Arg963Pro
NP_001119580.2:p.Arg955Pro
NP_001397825.1:p.Arg954Pro
NC_000016.9:g.56938314G>C

Protein change:

R954P

Molecular consequence:

NM_000339.3:c.2891G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001126107.2:c.2888G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001126108.2:c.2864G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001410896.1:c.2861G>C - 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
SCV004401275	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Nov 6, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 8528245, 17654016, 21415153, 22214629, 30596175, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004401275

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Nov 6, 2022)

germline

clinical testing

PubMed (6)
[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

Gitelman's variant of Bartter's syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter.

Simon DB, Nelson-Williams C, Bia MJ, Ellison D, Karet FE, Molina AM, Vaara I, Iwata F, Cushner HM, Koolen M, Gainza FJ, Gitleman HJ, Lifton RP.

Nat Genet. 1996 Jan;12(1):24-30.

PubMed [citation]

PMID:: 8528245

Novel mutations in the SLC12A3 gene causing Gitelman's syndrome in Swedes.

Fava C, Montagnana M, Rosberg L, Burri P, Jönsson A, Wanby P, Wahrenberg H, Hulthén UL, Aurell M, Guidi GC, Melander O.

DNA Seq. 2007 Oct;18(5):395-9.

PubMed [citation]

PMID:: 17654016

See all PubMed Citations (6)

Details of each submission

From Invitae, SCV004401275.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 964 of the SLC12A3 protein (p.Arg964Pro). 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. This variant disrupts the p.Arg964 amino acid residue in SLC12A3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8528245, 17654016, 21415153, 22214629, 30596175). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. This variant has not been reported in the literature in individuals affected with SLC12A3-related conditions. This variant is not present in population databases (gnomAD no frequency).

#	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: Feb 28, 2024

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