NM_001126108.2(SLC12A3):c.1743del (p.Met581fs) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 28, 2024
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:: RCV000406463.4

Allele description [Variation Report for NM_001126108.2(SLC12A3):c.1743del (p.Met581fs)]

NM_001126108.2(SLC12A3):c.1743del (p.Met581fs)

Gene:

SLC12A3:solute carrier family 12 member 3 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

16q13

Genomic location:

Preferred name:

NM_001126108.2(SLC12A3):c.1743del (p.Met581fs)

HGVS:

NC_000016.10:g.56884122del
NG_009386.1:g.23916del
NM_000339.3:c.1743del
NM_001126107.2:c.1740del
NM_001126108.2:c.1743delMANE SELECT
NP_000330.3:p.Met581fs
NP_001119579.2:p.Met580fs
NP_001119580.2:p.Met581fs
NC_000016.9:g.56918034del
NM_000339.2:c.1743delG

Protein change:

M580fs

Links:

dbSNP: rs754220610

NCBI 1000 Genomes Browser:

rs754220610

Molecular consequence:

NM_000339.3:c.1743del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001126107.2:c.1740del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001126108.2:c.1743del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Homo sapiens ATPase, H+ transporting, lysosomal 38kDa, V0 subunit d2, mRNA (cDNA...
Homo sapiens ATPase, H+ transporting, lysosomal 38kDa, V0 subunit d2, mRNA (cDNA clone MGC:70491 IMAGE:5190344), complete cds
gi|40807159|gb|BC065207.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000329743	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Pathogenic (Mar 29, 2016)	germline	clinical testing	Citation Link,
SCV003441995	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 28, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 20848653, 22009145, 25841442, 21415153, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000329743

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Pathogenic
(Mar 29, 2016)

germline

clinical testing

Citation Link,

SCV003441995

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 28, 2024)

germline

clinical testing

PubMed (5)
[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

Generation and analysis of the thiazide-sensitive Na+ -Cl- cotransporter (Ncc/Slc12a3) Ser707X knockin mouse as a model of Gitelman syndrome.

Yang SS, Lo YF, Yu IS, Lin SW, Chang TH, Hsu YJ, Chao TK, Sytwu HK, Uchida S, Sasaki S, Lin SH.

Hum Mutat. 2010 Dec;31(12):1304-15. doi: 10.1002/humu.21364. Epub 2010 Oct 14.

PubMed [citation]

PMID:: 20848653

Novel NCC mutants and functional analysis in a new cohort of patients with Gitelman syndrome.

Glaudemans B, Yntema HG, San-Cristobal P, Schoots J, Pfundt R, Kamsteeg EJ, Bindels RJ, Knoers NV, Hoenderop JG, Hoefsloot LH.

Eur J Hum Genet. 2012 Mar;20(3):263-70. doi: 10.1038/ejhg.2011.189. Epub 2011 Oct 19.

PubMed [citation]

PMID:: 22009145
PMCID:: PMC3283182

See all PubMed Citations (5)

Details of each submission

From GeneDx, SCV000329743.6

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

Description

The c.1743delG pathogenic variant in the SLC12A3 gene has been reported previously, along with a second pathogenic variant, in an individual with Gitelman syndrome (Vargas-Poussou et al., 2011). The c.1743delG variant causes a frameshift starting with codon Methionine 581, changes this amino acid to an Isoleucine residue, and creates a premature Stop codon at position 30 of the new reading frame, denoted p.Met581IlefsX30. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.1743delG variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.1743delG as a 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, SCV003441995.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change creates a premature translational stop signal (p.Met581Ilefs*30) in the SLC12A3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC12A3 are known to be pathogenic (PMID: 20848653, 22009145, 25841442). This variant is present in population databases (rs754220610, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with Gitelman syndrome (PMID: 21415153). ClinVar contains an entry for this variant (Variation ID: 280024). For these reasons, this variant has been classified as 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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