NM_001126108.2(SLC12A3):c.2186G>A (p.Gly729Asp) AND not provided

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Sep 22, 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:: RCV000412838.4

Allele description [Variation Report for NM_001126108.2(SLC12A3):c.2186G>A (p.Gly729Asp)]

NM_001126108.2(SLC12A3):c.2186G>A (p.Gly729Asp)

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.2186G>A (p.Gly729Asp)

HGVS:

NC_000016.10:g.56887932G>A
NG_009386.1:g.27726G>A
NM_000339.3:c.2186G>A
NM_001126107.2:c.2183G>A
NM_001126108.2:c.2186G>AMANE SELECT
NP_000330.3:p.Gly729Asp
NP_001119579.2:p.Gly728Asp
NP_001119580.2:p.Gly729Asp
NC_000016.9:g.56921844G>A
NM_000339.2:c.2186G>A

Protein change:

G728D

Links:

dbSNP: rs373901523

NCBI 1000 Genomes Browser:

rs373901523

Molecular consequence:

NM_000339.3:c.2186G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126107.2:c.2183G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126108.2:c.2186G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

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RecName: Full=Lymphocyte antigen 6F; Short=Ly-6F; AltName: Full=Ly-6F.1; Flags: ...
RecName: Full=Lymphocyte antigen 6F; Short=Ly-6F; AltName: Full=Ly-6F.1; Flags: Precursor
gi|547875|sp|P35460.1|LY6F_MOUSE

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000492095	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Likely pathogenic (Dec 1, 2016)	germline	clinical testing	Citation Link,
SCV003471556	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Sep 22, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 11168953, 17654016, 31672324, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000492095

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Likely pathogenic
(Dec 1, 2016)

germline

clinical testing

Citation Link,

SCV003471556

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Sep 22, 2023)

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	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

Gitelman's syndrome revisited: an evaluation of symptoms and health-related quality of life.

Cruz DN, Shaer AJ, Bia MJ, Lifton RP, Simon DB; Yale Gitelman's and Bartter's Syndrome Collaborative Study Group..

Kidney Int. 2001 Feb;59(2):710-7.

PubMed [citation]

PMID:: 11168953

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 (4)

Details of each submission

From GeneDx, SCV000492095.1

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

Description

The G729D variant in the SLC12A3 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The G729D variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G729D variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same residue (G729C, G729A, G729V) and in nearby residues (A728T, G731R) have been reported in the Human Gene Mutation Database in association with Gitelman syndrome (Stenson et al., 2014), supporting the functional importance of this residue and this region of the protein. We interpret G729D as a likely pathogenic variant.

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV003471556.2

#	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 aspartic acid, which is acidic and polar, at codon 729 of the SLC12A3 protein (p.Gly729Asp). This variant is present in population databases (rs373901523, gnomAD 0.002%). This missense change has been observed in individual(s) with Gitelman's syndrome (PMID: 31672324). ClinVar contains an entry for this variant (Variation ID: 373500). 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 disrupts the p.Gly729 amino acid residue in SLC12A3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11168953, 17654016, 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: Sep 29, 2024

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