NM_001126108.2(SLC12A3):c.2599G>A (p.Gly867Ser) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Jan 31, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV001756536.7

Allele description [Variation Report for NM_001126108.2(SLC12A3):c.2599G>A (p.Gly867Ser)]

NM_001126108.2(SLC12A3):c.2599G>A (p.Gly867Ser)

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.2599G>A (p.Gly867Ser)

HGVS:

NC_000016.10:g.56894608G>A
NG_009386.2:g.34402G>A
NM_000339.3:c.2626G>A
NM_001126107.2:c.2623G>A
NM_001126108.2:c.2599G>AMANE SELECT
NP_000330.3:p.Gly876Ser
NP_001119579.2:p.Gly875Ser
NP_001119580.2:p.Gly867Ser
NC_000016.9:g.56928520G>A
NG_009386.1:g.34402G>A
NM_000339.2:c.2626G>A

Protein change:

G867S

Links:

dbSNP: rs370301695

NCBI 1000 Genomes Browser:

rs370301695

Molecular consequence:

NM_000339.3:c.2626G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126107.2:c.2623G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126108.2:c.2599G>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
SCV001985414	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Apr 26, 2021)	germline	clinical testing	Citation Link,
SCV002307547	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jan 31, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 17654016, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001985414

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Apr 26, 2021)

germline

clinical testing

Citation Link,

SCV002307547

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jan 31, 2024)

germline

clinical testing

PubMed (2)
[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

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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From GeneDx, SCV001985414.2

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

Description

Observed in a patient with Gitelman syndrome in published literature (Fava et al., 2007); 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: 17654016)

#	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, SCV002307547.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 876 of the SLC12A3 protein (p.Gly876Ser). This variant is present in population databases (rs370301695, gnomAD 0.01%). This missense change has been observed in individuals with Gitelman syndrome (PMID: 17654016; Invitae). ClinVar contains an entry for this variant (Variation ID: 1303037). 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 80%. 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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