NM_001126108.2(SLC12A3):c.1925+1G>A AND not provided

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Apr 17, 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:: RCV001863199.4

Allele description [Variation Report for NM_001126108.2(SLC12A3):c.1925+1G>A]

NM_001126108.2(SLC12A3):c.1925+1G>A

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.1925+1G>A

HGVS:

NC_000016.10:g.56885365G>A
NG_009386.2:g.25159G>A
NM_000339.3:c.1925+1G>A
NM_001126107.2:c.1922+1G>A
NM_001126108.2:c.1925+1G>AMANE SELECT
NM_001410896.1:c.1922+1G>A
NC_000016.9:g.56919277G>A
NM_000339.2:c.1925+1G>A

Links:

dbSNP: rs1401379546

NCBI 1000 Genomes Browser:

rs1401379546

Molecular consequence:

NM_000339.3:c.1925+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001126107.2:c.1922+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001126108.2:c.1925+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001410896.1:c.1922+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

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
SCV002307153	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jul 1, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 18391953, 16199547, 20848653, 22009145, 25841442, 28492532
SCV004167651	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Apr 17, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002307153

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jul 1, 2022)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV004167651

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely pathogenic
(Apr 17, 2023)

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

Rare independent mutations in renal salt handling genes contribute to blood pressure variation.

Ji W, Foo JN, O'Roak BJ, Zhao H, Larson MG, Simon DB, Newton-Cheh C, State MW, Levy D, Lifton RP.

Nat Genet. 2008 May;40(5):592-599. doi: 10.1038/ng.118. Epub 2008 Apr 6.

PubMed [citation]

PMID:: 18391953
PMCID:: PMC3766631

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]

PMID:: 16199547
PMCID:: PMC1735933

See all PubMed Citations (6)

Details of each submission

From Invitae, SCV002307153.3

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

Description

Disruption of this splice site has been observed in individual(s) with Gitelman syndrome (PMID: 18391953). This variant is present in population databases (no rsID available, gnomAD 0.008%). This sequence change affects a donor splice site in intron 15 of the SLC12A3 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SLC12A3 are known to be pathogenic (PMID: 20848653, 22009145, 25841442). ClinVar contains an entry for this variant (Variation ID: 1028204). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site.

#	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, SCV004167651.1

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

Description

Identified in patients (phase unknown) with a second variant in the SLC12A3 gene in published literature (Ji et al., 2008); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 18391953)

#	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: Feb 14, 2024

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