ClinVar Genomic variation as it relates to human health
NM_000336.3(SCNN1B):c.1696C>T (p.Arg566Ter)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000336.3(SCNN1B):c.1696C>T (p.Arg566Ter)
Variation ID: 8830 Accession: VCV000008830.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16p12.2 16: 23380574 (GRCh38) [ NCBI UCSC ] 16: 23391895 (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 Oct 2, 2016 Sep 29, 2024 Feb 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000336.3:c.1696C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000327.2:p.Arg566Ter nonsense NC_000016.10:g.23380574C>T NC_000016.9:g.23391895C>T NG_011908.1:g.83305C>T - Protein change
- R566*
- Other names
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R564*
- Canonical SPDI
- NC_000016.10:23380573: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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Allele frequency
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The frequency of the allele represented by this VCV record.
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The Genome Aggregation Database (gnomAD) 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 | ||
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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
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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
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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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| SCNN1B | - | - |
GRCh38 GRCh37 |
309 | 343 | |
Conditions - Germline
| Condition
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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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| Pathogenic (2) |
criteria provided, single submitter
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Jun 23, 2016 | RCV000009378.5 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Feb 29, 2024 | RCV000713386.13 | |
| Pathogenic (1) |
criteria provided, single submitter
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Jan 27, 2022 | RCV002504771.1 |
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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Pathogenic
(Oct 15, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics
Accession: SCV000843986.2
First in ClinVar: Oct 20, 2018 Last updated: Dec 31, 2022 |
Comment:
This variant is expected to result in the loss of a functional protein. This variant results in a nonsense variant in the final exon of … (more)
This variant is expected to result in the loss of a functional protein. This variant results in a nonsense variant in the final exon of the gene which is not expected to trigger NMD, but which does eliminate the putatively important PY Motif. This variant was not reported in large, multi-ethnic, general populations (http://gnomad.broadinstitute.org). This variant segregates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant has been shown in studies to eliminate the protein domain needed for proper regulation, and thus greatly increase current through the sodium channel (PMID: 7777572). (less)
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Pathogenic
(Dec 06, 2018)
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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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000948280.4
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant has been reported to result in constitutive hyperactivity of the SCNN1B sodium channel … (more)
For these reasons, this variant has been classified as Pathogenic. This variant has been reported to result in constitutive hyperactivity of the SCNN1B sodium channel protein (PMID:7777572). This variant has been observed in several individuals with clinical features of Liddle syndrome (PMID: 27900368, 27896928, 26075967), and has been observed to segregate with Liddle syndrome in a family (PMID: 7954808). This variant is also known as p.Arg564* in the literature. ClinVar contains an entry for this variant (Variation ID: 8830). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the SCNN1B gene (p.Arg566*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 75 amino acids of the SCNN1B protein. (less)
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Pathogenic
(Feb 29, 2024)
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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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Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005198186.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
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Pathogenic
(Dec 28, 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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GeneDx
Accession: SCV001766997.2
First in ClinVar: Aug 07, 2021 Last updated: Sep 29, 2024 |
Comment:
Published functional studies demonstrate that the variant results in increased sodium channel activity (PMID: 7777572); Nonsense variant predicted to result in protein truncation, as the … (more)
Published functional studies demonstrate that the variant results in increased sodium channel activity (PMID: 7777572); Nonsense variant predicted to result in protein truncation, as the last 75 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27896928, 26075967, 9576123, 14645220, 28915228, 32561571, 24474657, 11478429, 10362597, 24093724, 7954808, 27900368, 7777572) (less)
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Pathogenic
(Jun 23, 2016)
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criteria provided, single submitter
Method: clinical testing
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Liddle syndrome 1
This variant was identified in an
(more...)
Affected status: yes
Allele origin:
inherited
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Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine
Accession: SCV000282671.2
First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016 |
Number of individuals with the variant: 2
Clinical Features:
Hypertension (present) , Hypokalemia (present) , Metabolic alkalosis (present) , Decreased circulating renin level (present) , Pseudohypoaldosteronism (present)
Family history: yes
Age: 0-9 years
Sex: female
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Pathogenic
(Jan 27, 2022)
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criteria provided, single submitter
Method: clinical testing
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Liddle syndrome 1
Bronchiectasis with or without elevated sweat chloride 1 Pseudohypoaldosteronism, type IB1, autosomal recessive
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002816666.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Nov 04, 1994)
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no assertion criteria provided
Method: literature only
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LIDDLE SYNDROME 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000029596.3
First in ClinVar: Apr 04, 2013 Last updated: Sep 16, 2018 |
Comment on evidence:
After demonstrating complete linkage between the SCNN1B gene and Liddle syndrome (LIDLS1; 177200) in the pedigree originally described by Liddle et al. (1963), Shimkets et … (more)
After demonstrating complete linkage between the SCNN1B gene and Liddle syndrome (LIDLS1; 177200) in the pedigree originally described by Liddle et al. (1963), Shimkets et al. (1994) identified a causative premature stop codon in the SCNN1B gene. A C-to-T transition at the first nucleotide of codon 564 resulted in the stop codon and deletion of the last 75 amino acids from the encoded protein (arg564 to ter; R564X). This truncation left the second transmembrane domain intact but removed virtually the entire cytoplasmic carboxyl tail of the protein. (less)
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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
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Analysis of the genes involved in Mendelian forms of low-renin hypertension in Chinese early-onset hypertensive patients. | Liu K | Journal of hypertension | 2018 | PMID: 28915228 |
| Liddle syndrome: clinical and genetic profiles. | Cui Y | Journal of clinical hypertension (Greenwich, Conn.) | 2017 | PMID: 27896928 |
| Whole-exome sequencing reveals an inherited R566X mutation of the epithelial sodium channel β-subunit in a case of early-onset phenotype of Liddle syndrome. | Polfus LM | Cold Spring Harbor molecular case studies | 2016 | PMID: 27900368 |
| Prevalence of Liddle Syndrome Among Young Hypertension Patients of Undetermined Cause in a Chinese Population. | Wang LP | Journal of clinical hypertension (Greenwich, Conn.) | 2015 | PMID: 26075967 |
| Phenotype-genotype analysis in two Chinese families with Liddle syndrome. | Gong L | Molecular biology reports | 2014 | PMID: 24474657 |
| Hypoxia-induced inhibition of epithelial Na(+) channels in the lung. Role of Nedd4-2 and the ubiquitin-proteasome pathway. | Gille T | American journal of respiratory cell and molecular biology | 2014 | PMID: 24093724 |
| Relative contribution of Nedd4 and Nedd4-2 to ENaC regulation in epithelia determined by RNA interference. | Snyder PM | The Journal of biological chemistry | 2004 | PMID: 14645220 |
| A family with liddle's syndrome caused by a mutation in the beta subunit of the epithelial sodium channel. | Kyuma M | Clinical and experimental hypertension (New York, N.Y. : 1993) | 2001 | PMID: 11478429 |
| Effect of subunit composition and Liddle's syndrome mutations on biosynthesis of ENaC. | Prince LS | The American journal of physiology | 1999 | PMID: 10362597 |
| Mutations and variants of the epithelial sodium channel gene in Liddle's syndrome and primary hypertension. | Melander O | Hypertension (Dallas, Tex. : 1979) | 1998 | PMID: 9576123 |
| A mutation in the epithelial sodium channel causing Liddle disease increases channel activity in the Xenopus laevis oocyte expression system. | Schild L | Proceedings of the National Academy of Sciences of the United States of America | 1995 | PMID: 7777572 |
| Liddle's syndrome: heritable human hypertension caused by mutations in the beta subunit of the epithelial sodium channel. | Shimkets RA | Cell | 1994 | PMID: 7954808 |
| Liddle, G. W., Bledsoe, T., Coppage, W. S., Jr. A familial renal disorder simulating primary aldosteronism but with negligible aldosterone secretion. Trans. Assoc. Am. Phys. 76: 199-213, 1963. | - | - | - | - |
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Text-mined citations for rs137852704 ...
HelpRecord last updated Sep 29, 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.