ClinVar Genomic variation as it relates to human health
NM_001126108.2(SLC12A3):c.965C>T (p.Ala322Val)
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.
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.
Uncertain significance(7); Likely benign(5)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001126108.2(SLC12A3):c.965C>T (p.Ala322Val)
Variation ID: 498813 Accession: VCV000498813.37
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16q13 16: 56872656 (GRCh38) [ NCBI UCSC ] 16: 56906568 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 2, 2018 Aug 4, 2024 Jan 30, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001126108.2:c.965C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001119580.2:p.Ala322Val missense NM_000339.3:c.965C>T NP_000330.3:p.Ala322Val missense NM_001126107.2:c.962C>T NP_001119579.2:p.Ala321Val missense NC_000016.10:g.56872656C>T NC_000016.9:g.56906568C>T NG_009386.1:g.12450C>T - Protein change
- A322V, A321V
- Other names
- p.Ala322Val
- Canonical SPDI
- NC_000016.10:56872655:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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0.00100 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00078
1000 Genomes Project 0.00100
Exome Aggregation Consortium (ExAC) 0.00142
The Genome Aggregation Database (gnomAD) 0.00157
Trans-Omics for Precision Medicine (TOPMed) 0.00169
The Genome Aggregation Database (gnomAD), exomes 0.00173
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00215
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 | ||
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HI score
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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. |
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SLC12A3 | - | - |
GRCh38 GRCh37 |
1623 | 1717 |
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. |
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Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
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Jan 30, 2024 | RCV000591358.27 | |
Uncertain significance (5) |
criteria provided, multiple submitters, no conflicts
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Apr 27, 2022 | RCV000989608.11 | |
Likely benign (1) |
criteria provided, single submitter
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Dec 15, 2023 | RCV003488715.1 | |
Likely benign (1) |
criteria provided, single submitter
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Oct 13, 2022 | RCV004024751.1 | |
SLC12A3-related disorder
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Likely benign (1) |
criteria provided, single submitter
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Mar 9, 2022 | RCV003935605.1 |
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. |
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Uncertain significance
(Nov 23, 2016)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000704020.2
First in ClinVar: Apr 02, 2018 Last updated: Apr 02, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Uncertain significance
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Familial hypokalemia-hypomagnesemia
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001140112.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Uncertain significance
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Familial hypokalemia-hypomagnesemia
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001276802.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Likely benign
(Jan 30, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001029316.6
First in ClinVar: Dec 17, 2019 Last updated: Feb 14, 2024 |
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Uncertain significance
(May 18, 2021)
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criteria provided, single submitter
Method: clinical testing
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Familial hypokalemia-hypomagnesemia
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV001716396.1
First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021 |
Sex: mixed
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Uncertain significance
(Apr 27, 2022)
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criteria provided, single submitter
Method: clinical testing
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Familial hypokalemia-hypomagnesemia
Affected status: yes
Allele origin:
germline
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European Hospital Georges Pompidou Genetics Department, Assistance Publique - Hôpitaux de Paris AP-HP
Accession: SCV002513851.1
First in ClinVar: May 21, 2022 Last updated: May 21, 2022
Comment:
ACMG criteria used:PM1 PM2 BS2, BP2
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Comment:
ACMG criteria used:PM1 PM2 BS2, BP2
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Uncertain significance
(May 26, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001874870.3
First in ClinVar: Sep 19, 2021 Last updated: Mar 04, 2023 |
Comment:
Reported along with a second variant in the SLC12A3 gene in two patients with Gitelman syndrome in the published literature; however, segregation information was not … (more)
Reported along with a second variant in the SLC12A3 gene in two patients with Gitelman syndrome in the published literature; however, segregation information was not provided (Vargas-Poussou R et al., 2011); Reported as a variant of uncertain clinical significance along with two additional SLC12A3 variants in an individual referred from a nephrology clinic; however specific phenotype and segregation information was not provided (Vaisitti et al., 2020); Reported as a single heterozygous variant in an individual with salt-wasting congenital adrenal hyperplasia with subsequent hypokalemia; a homozygous pathogenic variant in CYP21A was also identified (Calcaterra et al., 2021); 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: 33226606, 33763274, 21415153, 34426522) (less)
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Uncertain significance
(Feb 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004227588.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
BP4, PM3
Number of individuals with the variant: 8
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Likely benign
(Dec 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004241541.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
Comment:
Variant summary: SLC12A3 c.965C>T (p.Ala322Val) results in a non-conservative amino acid change located in the Amino acid permease/ SLC12A domain of the encoded protein sequence. … (more)
Variant summary: SLC12A3 c.965C>T (p.Ala322Val) results in a non-conservative amino acid change located in the Amino acid permease/ SLC12A domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0017 in 251454 control chromosomes in the gnomAD database, including 6 homozygotes. c.965C>T has been reported in the literature in individuals affected with Familial Hypokalemia-Hypomagnesemia (Vargas-Poussou_2011). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Hypokalemia-Hypomagnesemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 21415153). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as likely benign. (less)
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Likely benign
(Mar 09, 2022)
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criteria provided, single submitter
Method: clinical testing
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SLC12A3-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004755786.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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Likely benign
(Oct 13, 2022)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV004951101.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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Likely benign
(Feb 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004139420.8
First in ClinVar: Nov 20, 2023 Last updated: Aug 04, 2024 |
Comment:
SLC12A3: BP4, BS2
Number of individuals with the variant: 1
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Benign
(Jan 09, 2020)
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no assertion criteria provided
Method: clinical testing
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Gitelman syndrome
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001458553.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Congenital Adrenal Hyperplasia (CAH) and Gitelman Syndrome (GS): Overlapping Symptoms in an Uncommon Association. | Calcaterra V | Case reports in pediatrics | 2021 | PMID: 33763274 |
Clinical exome sequencing is a powerful tool in the diagnostic flow of monogenic kidney diseases: an Italian experience. | Vaisitti T | Journal of nephrology | 2021 | PMID: 33226606 |
Spectrum of mutations in Gitelman syndrome. | Vargas-Poussou R | Journal of the American Society of Nephrology : JASN | 2011 | PMID: 21415153 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SLC12A3 | - | - | - | - |
Text-mined citations for rs142679083 ...
HelpRecord last updated Aug 04, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.