ClinVar Genomic variation as it relates to human health
NM_001354761.2(ADD1):c.1378G>T (p.Gly460Trp)
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_001354761.2(ADD1):c.1378G>T (p.Gly460Trp)
Variation ID: 18274 Accession: VCV000018274.4
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 4p16.3 4: 2904980 (GRCh38) [ NCBI UCSC ] 4: 2906707 (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 4, 2013 Dec 12, 2021 Mar 24, 2021 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001354761.2:c.1378G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001341690.1:p.Gly460Trp missense NM_001119.5:c.1378G>T NP_001110.2:p.Gly460Trp missense NM_001286645.2:c.1378G>T NP_001273574.1:p.Gly460Trp missense NM_001354754.2:c.1378G>T NP_001341683.1:p.Gly460Trp missense NM_001354755.2:c.1378G>T NP_001341684.1:p.Gly460Trp missense NM_001354756.2:c.1378G>T NP_001341685.1:p.Gly460Trp missense NM_001354757.2:c.1378G>T NP_001341686.1:p.Gly460Trp missense NM_001354758.2:c.1378G>T NP_001341687.1:p.Gly460Trp missense NM_001354759.2:c.1378G>T NP_001341688.1:p.Gly460Trp missense NM_001354762.2:c.1378G>T NP_001341691.1:p.Gly460Trp missense NM_014189.4:c.1378G>T NP_054908.2:p.Gly460Trp missense NM_014190.4:c.1378G>T NP_054909.2:p.Gly460Trp missense NM_176801.3:c.1378G>T NP_789771.1:p.Gly460Trp missense NC_000004.12:g.2904980G>T NC_000004.11:g.2906707G>T NG_012037.1:g.66124G>T P35611:p.Gly460Trp - Protein change
- G460W
- Other names
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- Canonical SPDI
- NC_000004.12:2904979:G: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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0.20847 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.16268
Trans-Omics for Precision Medicine (TOPMed) 0.16804
1000 Genomes Project 30x 0.20050
Exome Aggregation Consortium (ExAC) 0.20187
1000 Genomes Project 0.20847
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
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. |
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ADD1 | - | - |
GRCh38 GRCh37 |
43 | 168 |
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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risk factor (1) |
no assertion criteria provided
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Feb 1, 1999 | RCV000019936.10 | |
drug response (1) |
reviewed by expert panel
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Mar 24, 2021 | RCV001787814.9 |
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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drug response
(Mar 24, 2021)
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reviewed by expert panel
Method: curation
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hydrochlorothiazide response - Efficacy
Drug used for
Essential hypertension
, and Hypertension
Affected status: yes
Allele origin:
germline
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PharmGKB
Accession: SCV002031261.1
First in ClinVar: Dec 12, 2021 Last updated: Dec 12, 2021
Comment:
Drug is not necessarily used to treat response condition
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Comment:
PharmGKB Level of Evidence 2B: Variants in Level 2B clinical annotations are not in PharmGKB’s Tier 1 VIPs. These clinical annotations describe variant-drug combinations with … (more)
PharmGKB Level of Evidence 2B: Variants in Level 2B clinical annotations are not in PharmGKB’s Tier 1 VIPs. These clinical annotations describe variant-drug combinations with a moderate level of evidence supporting the association. For example, the association may be found in multiple cohorts, but there may be a minority of studies that do not support the majority assertion. Level 2B clinical annotations must be supported by at least two independent publications. (less)
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risk factor
(Feb 01, 1999)
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no assertion criteria provided
Method: literature only
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HYPERTENSION, SALT-SENSITIVE ESSENTIAL, SUSCEPTIBILITY TO
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000040234.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
Cusi et al. (1997) found a significant association between a gly460-to-trp polymorphism (G460W) in the ADD1 gene and salt sensitivity in patients with essential hypertension … (more)
Cusi et al. (1997) found a significant association between a gly460-to-trp polymorphism (G460W) in the ADD1 gene and salt sensitivity in patients with essential hypertension (see 145500). Patients with the W460 allele showed greater sensitivity to changes in sodium balance, and heterozygous hypertensive patients (G/W) showed a greater fall in mean arterial pressure in response to 2 months' treatment with hydrochlorothiazide, than did wildtype homozygous (G/G) hypertensive patients. In controls in an Italian cohort, the G460 allele had a frequency of 86.4% and the W460 allele 13.6%. Manunta et al. (1998) analyzed the pressure-natriuresis relationship in 108 hypertensive individuals, 80 of whom were wildtype homozygous (G/G), 26 G/W heterozygous, and 2 W/W homozygous. At baseline, the G/W and W/W patients showed lower plasma renin activity and fractional excretion of sodium; these patients also had reduced slope of the pressure-natriuresis relationship after sodium depletion or sodium loading compared to G/G patients. These findings supported the hypothesis that individuals with at least 1 ADD1 460W allele have increased renal tubular sodium reabsorption. Using endogenous lithium and uric acid as markers of proximal tubular sodium reabsorption, Manunta et al. (1999) investigated the relationship between renal sodium handling and ADD1 polymorphism in 54 untreated hypertensive patients, 29 with the G/G genotype and 25 with the G/W genotype. Fractional excretions of lithium and uric acid were significantly decreased in G/W patients compared to G/G patients; multiple regression analysis showed that adducin genotype was significantly and directly related to the fractional excretion of lithium. Manunta et al. (1999) concluded that ADD1 represents a 'renal hypertensive gene' that modulates the capacity of tubular epithelial cells to transport sodium and thus affects blood pressure levels. (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
HelpTitle | Author | Journal | Year | Link |
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Effects of ACE and ADD1 gene polymorphisms on blood pressure response to hydrochlorothiazide: a meta-analysis. | Choi HD | International journal of clinical pharmacology and therapeutics | 2013 | PMID: 23863317 |
Renin-angiotensin system and alpha-adducin gene polymorphisms and their relation to responses to antihypertensive drugs: results from the GENRES study. | Suonsyrjä T | American journal of hypertension | 2009 | PMID: 19057513 |
Physiological interaction between alpha-adducin and WNK1-NEDD4L pathways on sodium-related blood pressure regulation. | Manunta P | Hypertension (Dallas, Tex. : 1979) | 2008 | PMID: 18591455 |
Effects of endothelial nitric oxide synthase, alpha-adducin, and other candidate gene polymorphisms on blood pressure response to hydrochlorothiazide. | Turner ST | American journal of hypertension | 2003 | PMID: 14553962 |
ACE and alpha-adducin polymorphism as markers of individual response to diuretic therapy. | Sciarrone MT | Hypertension (Dallas, Tex. : 1979) | 2003 | PMID: 12623934 |
alpha-Adducin 460Trp allele is associated with erythrocyte Na transport rate in North Sardinian primary hypertensives. | Glorioso N | Hypertension (Dallas, Tex. : 1979) | 2002 | PMID: 11882573 |
The role of alpha-adducin polymorphism in blood pressure and sodium handling regulation may not be excluded by a negative association study. | Glorioso N | Hypertension (Dallas, Tex. : 1979) | 1999 | PMID: 10523341 |
Adducin polymorphism affects renal proximal tubule reabsorption in hypertension. | Manunta P | Hypertension (Dallas, Tex. : 1979) | 1999 | PMID: 10024330 |
Alpha-adducin polymorphisms and renal sodium handling in essential hypertensive patients. | Manunta P | Kidney international | 1998 | PMID: 9607177 |
Polymorphisms of alpha-adducin and salt sensitivity in patients with essential hypertension. | Cusi D | Lancet (London, England) | 1997 | PMID: 9149697 |
https://www.pharmgkb.org/clinicalAnnotation/981202714 | - | - | - | - |
https://www.pharmgkb.org/variant/PA166156480 | - | - | - | - |
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Text-mined citations for rs4961 ...
HelpRecord last updated May 01, 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.