This variant has not been reported in the literature in individuals affected with WNK1-related conditions. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 617550). This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Gln974*) in the WNK1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in WNK1 are known to be pathogenic (PMID: 22910560).
ClinVar Genomic variation as it relates to human health
NM_213655.5(WNK1):c.2920C>T (p.Gln974Ter)
Germline
Classification
Help
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.
(4)
Help
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
4
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_213655.5(WNK1):c.2920C>T (p.Gln974Ter)
Variation ID: 617550 Accession: VCV000617550.7
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 12p13.33 12: 868391 (GRCh38) [ NCBI UCSC ] 12: 977557 (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 Jul 24, 2019 Nov 24, 2024 Jul 17, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_018979.4:c.2140-2874C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_213655.5:c.2920C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_998820.3:p.Gln974Ter nonsense NM_001184985.2:c.2665C>T NP_001171914.1:p.Gln889Ter nonsense NM_014823.3:c.2140-2874C>T intron variant NM_213655.4:c.2920C>T NC_000012.12:g.868391C>T NC_000012.11:g.977557C>T NG_007984.3:g.120333C>T LRG_247:g.120333C>T LRG_247t1:c.2140-2874C>T LRG_247t2:c.2920C>T LRG_247p2:p.Gln974Ter - Protein change
- Q974*, Q889*
- Other names
- -
- Canonical SPDI
- NC_000012.12:868390:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
protein truncation; Variation Ontology [ VariO:0015]
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| WNK1 | - | - |
GRCh38 GRCh37 |
1923 | 2020 | |
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. |
|---|---|---|---|---|
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jul 17, 2023 | RCV000788052.4 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Nov 8, 2022 | RCV001869016.4 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(May 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Neuropathy, hereditary sensory and autonomic, type 2A
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001138619.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
|
|
|
Pathogenic
(Nov 08, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Neuropathy, hereditary sensory and autonomic, type 2A
Pseudohypoaldosteronism type 2C
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002235620.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 28, 2024 |
Comment:
This variant has not been reported in the literature in individuals affected with WNK1-related conditions. For these reasons, this variant has been classified as Pathogenic. … (more)
This variant has not been reported in the literature in individuals affected with WNK1-related conditions. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 617550). This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Gln974*) in the WNK1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in WNK1 are known to be pathogenic (PMID: 22910560). (less)
|
|
|
Pathogenic
(Jul 17, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Neuropathy, hereditary sensory and autonomic, type 2A
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV005400317.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with neuropathy, hereditary sensory and autonomic, type II (HSAN; MIM#201300), and pseudohypoaldosteronism, type IIC (PHA2C; MIM#614492), respectively. Variants resulting in a premature termination codon have a loss of function mechanism. Intronic deletions and missense variants within the acidic wnk motif result in increased protein expression and gain of function (PMID: 32790646, PMID: 11498583). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (3 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported more recently as pathogenic, and in individuals with neuropathy, hereditary sensory and autonomic, type II (HSAN) (ClinVar, PMID: 30497409). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic, where one individual was confirmed to be homozygous (ClinVar). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
|
|
|
Pathogenic
(Feb 14, 2018)
|
no assertion criteria provided
Method: clinical testing
|
Neuropathy, hereditary sensory and autonomic, type 2A
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
unknown
|
Department of Neurology, Hospital Garcia de Orta
Accession: SCV000882432.1
First in ClinVar: Jul 24, 2019 Last updated: Jul 24, 2019 |
Clinical Features:
Hereditary Sensory and Autonomic type 2 (present)
Age: 30-39 years
Sex: female
Ethnicity/Population group: African
Geographic origin: Cape Verde
Method: DNA semi-quantitative and integrity evaluation (automated extraction) (PT56/1); PCR and Next Generation Sequencing; qPCR or MLPA
Testing laboratory: IBMC/CGPP
Date variant was reported to submitter: 2018-02-14
Testing laboratory interpretation: Pathogenic
|
Comment:
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with neuropathy, hereditary sensory and autonomic, type II (HSAN; MIM#201300), and pseudohypoaldosteronism, type IIC (PHA2C; MIM#614492), respectively. Variants resulting in a premature termination codon have a loss of function mechanism. Intronic deletions and missense variants within the acidic wnk motif result in increased protein expression and gain of function (PMID: 32790646, PMID: 11498583). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (3 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported more recently as pathogenic, and in individuals with neuropathy, hereditary sensory and autonomic, type II (HSAN) (ClinVar, PMID: 30497409). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic, where one individual was confirmed to be homozygous (ClinVar). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Germline Functional Evidence
| Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|---|---|---|---|---|
|
protein truncation
|
Department of Neurology, Hospital Garcia de Orta
Accession: SCV000882432.1
|
|
Comment:
This variant has not been reported in the literature in individuals affected with WNK1-related conditions. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 617550). This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Gln974*) in the WNK1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in WNK1 are known to be pathogenic (PMID: 22910560).
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with neuropathy, hereditary sensory and autonomic, type II (HSAN; MIM#201300), and pseudohypoaldosteronism, type IIC (PHA2C; MIM#614492), respectively. Variants resulting in a premature termination codon have a loss of function mechanism. Intronic deletions and missense variants within the acidic wnk motif result in increased protein expression and gain of function (PMID: 32790646, PMID: 11498583). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (3 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported more recently as pathogenic, and in individuals with neuropathy, hereditary sensory and autonomic, type II (HSAN) (ClinVar, PMID: 30497409). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic, where one individual was confirmed to be homozygous (ClinVar). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Mutation affecting the conserved acidic WNK1 motif causes inherited hyperkalemic hyperchloremic acidosis. | Louis-Dit-Picard H | The Journal of clinical investigation | 2020 | PMID: 32790646 |
| A novel nonsense mutation in WNK1/HSN2 associated with sensory neuropathy and limb destruction in four siblings of a large Iranian pedigree. | Rahmani B | BMC neurology | 2018 | PMID: 30497409 |
| A novel homozygous mutation in the WNK1/HSN2 gene causing hereditary sensory neuropathy type 2. | Potulska-Chromik A | Acta biochimica Polonica | 2012 | PMID: 22910560 |
| Human hypertension caused by mutations in WNK kinases. | Wilson FH | Science (New York, N.Y.) | 2001 | PMID: 11498583 |
Text-mined citations for rs1478989689 ...
HelpThese 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 Nov 30, 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.