VCV000403447.37 - ClinVar

NM_001126108.2(SLC12A3):c.2182G>A (p.Ala728Thr)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(11)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Benign/Likely benign

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001126108.2(SLC12A3):c.2182G>A (p.Ala728Thr)

Variation ID: 403447 Accession: VCV000403447.37

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 16q13 16: 56887928 (GRCh38) [ NCBI UCSC ] 16: 56921840 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 9, 2017	Oct 20, 2024	Feb 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001126108.2:c.2182G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001119580.2:p.Ala728Thr	missense
NM_000339.3:c.2182G>A	NP_000330.3:p.Ala728Thr	missense
NM_001126107.2:c.2179G>A	NP_001119579.2:p.Ala727Thr	missense
NC_000016.10:g.56887928G>A
NC_000016.9:g.56921840G>A
NG_009386.2:g.27722G>A

... more HGVS ... less HGVS

Protein change

A728T, A727T

Other names

Canonical SPDI

NC_000016.10:56887927:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00599 (A)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 0.00599

1000 Genomes Project 30x 0.00640

The Genome Aggregation Database (gnomAD) 0.01075

Exome Aggregation Consortium (ExAC) 0.01211

The Genome Aggregation Database (gnomAD), exomes 0.01212

Trans-Omics for Precision Medicine (TOPMed) 0.01292

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.01447

Links

ClinGen: CA8069786 dbSNP: rs36049418 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
SLC12A3		-	-	GRCh38 GRCh37	1632	1726

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not specified	Likely benign (3)	criteria provided, single submitter	Mar 28, 2016	RCV000455191.8
Familial hypokalemia-hypomagnesemia	Benign/Likely benign (4)	criteria provided, multiple submitters, no conflicts	Jul 15, 2021	RCV001120452.10
not provided	Benign/Likely benign (4)	criteria provided, multiple submitters, no conflicts	Feb 1, 2024	RCV001520029.21

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely benign (Mar 28, 2016)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000540355.1 First in ClinVar: Apr 09, 2017 Last updated: Apr 09, 2017	Comment: Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or … (more) Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 188/12996=1.44% (less) Method: Genome/Exome Filtration
Likely benign (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Familial hypokalemia-hypomagnesemia Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001278936.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (1) PubMed: 8528245 Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Familial hypokalemia-hypomagnesemia (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV001435124.1 First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020	Comment: The heterozygous p.Ala728Thr variant in SLC12A3 has been identified in an individual from the Philippines with Gitelman syndrome (PMID: 8528245), but has also been identified … (more) The heterozygous p.Ala728Thr variant in SLC12A3 has been identified in an individual from the Philippines with Gitelman syndrome (PMID: 8528245), but has also been identified in >1% of European (non-Finnish) chromosomes and 27 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for autosomal recessive Gitelman syndrome. (less)
Benign (Jan 26, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001757212.1 First in ClinVar: Jul 24, 2021 Last updated: Jul 24, 2021	Comment: This variant is associated with the following publications: (PMID: 27535533, 27884173, 8528245, 20981092, 24633158)
Benign (Jul 15, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial hypokalemia-hypomagnesemia Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002055378.1 First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022
Benign (Feb 01, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001729023.4 First in ClinVar: Jun 15, 2021 Last updated: Feb 20, 2024
Likely benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005216522.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Benign (Jan 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004010490.12 First in ClinVar: Jul 16, 2023 Last updated: Oct 20, 2024	Comment: SLC12A3: BP4, BS1, BS2 Number of individuals with the variant: 4
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001929413.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001955199.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Benign (Oct 25, 2019)	no assertion criteria provided Method: clinical testing	Gitelman syndrome Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002089370.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022
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Comment:

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 188/12996=1.44%

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Comment:

The heterozygous p.Ala728Thr variant in SLC12A3 has been identified in an individual from the Philippines with Gitelman syndrome (PMID: 8528245), but has also been identified in >1% of European (non-Finnish) chromosomes and 27 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for autosomal recessive Gitelman syndrome.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Gitelman's variant of Bartter's syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter.	Simon DB	Nature genetics	1996	PMID: 8528245

Text-mined citations for rs36049418 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_001126108.2(SLC12A3):c.2182G>A (p.Ala728Thr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs36049418 ...