VCV000631753.16 - ClinVar

NM_001126108.2(SLC12A3):c.1390G>A (p.Ala464Thr)

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.

(5)

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.

Pathogenic/Likely pathogenic

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.1390G>A (p.Ala464Thr)

Variation ID: 631753 Accession: VCV000631753.16

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 16q13 16: 56879596 (GRCh38) [ NCBI UCSC ] 16: 56913508 (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	May 27, 2019	Feb 14, 2024	Dec 27, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001126108.2:c.1390G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001119580.2:p.Ala464Thr	missense
NM_000339.3:c.1390G>A	NP_000330.3:p.Ala464Thr	missense
NM_001126107.2:c.1387G>A	NP_001119579.2:p.Ala463Thr	missense
NC_000016.10:g.56879596G>A
NC_000016.9:g.56913508G>A
NG_009386.1:g.19390G>A

... more HGVS ... less HGVS

Protein change

A464T, A463T

Other names

Canonical SPDI

NC_000016.10:56879595: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.

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

Exome Aggregation Consortium (ExAC) 0.00002

Trans-Omics for Precision Medicine (TOPMed) 0.00002

The Genome Aggregation Database (gnomAD) 0.00006

Links

dbSNP: rs201945662 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.
Familial hypokalemia-hypomagnesemia	Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Apr 27, 2022	RCV000778472.10
not provided	Pathogenic (1)	criteria provided, single submitter	Dec 27, 2023	RCV001224209.8

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 pathogenic (Dec 18, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019) Method: clinical testing	Familial hypokalemia-hypomagnesemia Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000914728.1 First in ClinVar: May 27, 2019 Last updated: May 27, 2019	Publications: PubMed (6) PubMed: 22009145‚ 21415153‚ 21753071‚ 17699451‚ 23328711‚ 12112667 Comment: The SLC12A3 c.1390G>A (p.Ala464Thr) variant has been reported in ten individuals with Gitelman syndrome (SyrÃ©n et al. 2002; Colussi et al. 2007; Vargas-Poussou et al. … (more) The SLC12A3 c.1390G>A (p.Ala464Thr) variant has been reported in ten individuals with Gitelman syndrome (SyrÃ©n et al. 2002; Colussi et al. 2007; Vargas-Poussou et al. 2011; Balavoine et al. 2011; Glaudemans et al. 2012; Berry et al. 2013), including in a homozygous state in one patient, in a compound heterozygous state in four patients, and in a heterozygous state in five patients in whom a second variant was not identified. Vargas-Poussou et al. (2011) note that 18 to 40% of patients with suspected Gitelman syndrome carry only one SLC12A3 variant allele. The p.Ala464Thr variant was absent from 100 control alleles and is reported at a frequency of 0.000012 in the Total population of the Genome Aggregation Database. Functional studies of the variant have not been conducted. Based on the collective evidence, the p.Ala464Thr variant is classified as likely pathogenic for Gitelman syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
Likely pathogenic (Apr 27, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial hypokalemia-hypomagnesemia Affected status: yes Allele origin: germline	European Hospital Georges Pompidou Genetics Department, Assistance Publique - Hôpitaux de Paris AP-HP Accession: SCV002513806.1 First in ClinVar: May 21, 2022 Last updated: May 21, 2022 Comment: ACMG criteria used:PS4, PM1, PM2, PP3, PP5,	Comment: ACMG criteria used:PS4, PM1, PM2, PP3, PP5,
Likely pathogenic (Jan 05, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial hypokalemia-hypomagnesemia Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002800232.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Dec 27, 2023)	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: SCV001396393.5 First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 17699451‚ 21415153‚ 21753071‚ 22009145 Comment: This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 464 of the SLC12A3 protein (p.Ala464Thr). … (more) This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 464 of the SLC12A3 protein (p.Ala464Thr). This variant is present in population databases (rs201945662, gnomAD 0.007%). This missense change has been observed in individuals with Gitelman syndrome (PMID: 17699451, 21415153, 21753071, 22009145). ClinVar contains an entry for this variant (Variation ID: 631753). 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%. For these reasons, this variant has been classified as Pathogenic. (less)
Likely pathogenic (Mar 29, 2020)	no assertion criteria provided Method: clinical testing	Gitelman syndrome Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002089350.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022

Comment:

The SLC12A3 c.1390G>A (p.Ala464Thr) variant has been reported in ten individuals with Gitelman syndrome (SyrÃ©n et al. 2002; Colussi et al. 2007; Vargas-Poussou et al. 2011; Balavoine et al. 2011; Glaudemans et al. 2012; Berry et al. 2013), including in a homozygous state in one patient, in a compound heterozygous state in four patients, and in a heterozygous state in five patients in whom a second variant was not identified. Vargas-Poussou et al. (2011) note that 18 to 40% of patients with suspected Gitelman syndrome carry only one SLC12A3 variant allele. The p.Ala464Thr variant was absent from 100 control alleles and is reported at a frequency of 0.000012 in the Total population of the Genome Aggregation Database. Functional studies of the variant have not been conducted. Based on the collective evidence, the p.Ala464Thr variant is classified as likely pathogenic for Gitelman syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Comment:

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 464 of the SLC12A3 protein (p.Ala464Thr). This variant is present in population databases (rs201945662, gnomAD 0.007%). This missense change has been observed in individuals with Gitelman syndrome (PMID: 17699451, 21415153, 21753071, 22009145). ClinVar contains an entry for this variant (Variation ID: 631753). 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%. For these reasons, this variant has been classified as Pathogenic.

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
Unexpected clinical sequelae of Gitelman syndrome: hypertension in adulthood is common and females have higher potassium requirements.	Berry MR	Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association	2013	PMID: 23328711
Novel NCC mutants and functional analysis in a new cohort of patients with Gitelman syndrome.	Glaudemans B	European journal of human genetics : EJHG	2012	PMID: 22009145
Phenotype-genotype correlation and follow-up in adult patients with hypokalaemia of renal origin suggesting Gitelman syndrome.	Balavoine AS	European journal of endocrinology	2011	PMID: 21753071
Spectrum of mutations in Gitelman syndrome.	Vargas-Poussou R	Journal of the American Society of Nephrology : JASN	2011	PMID: 21415153
A thiazide test for the diagnosis of renal tubular hypokalemic disorders.	Colussi G	Clinical journal of the American Society of Nephrology : CJASN	2007	PMID: 17699451
Identification of fifteen novel mutations in the SLC12A3 gene encoding the Na-Cl Co-transporter in Italian patients with Gitelman syndrome.	Syrén ML	Human mutation	2002	PMID: 12112667

Text-mined citations for rs201945662 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_001126108.2(SLC12A3):c.1390G>A (p.Ala464Thr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs201945662 ...