ClinVar Genomic variation as it relates to human health
NM_005214.5(CTLA4):c.49A>G (p.Thr17Ala)
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
-
NM_005214.5(CTLA4):c.49A>G (p.Thr17Ala)
Variation ID: 16921 Accession: VCV000016921.14
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 2q33.2 2: 203867991 (GRCh38) [ NCBI UCSC ] 2: 204732714 (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 Apr 9, 2017 Feb 20, 2024 Feb 1, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_005214.5:c.49A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005205.2:p.Thr17Ala missense NM_001037631.3:c.49A>G NP_001032720.1:p.Thr17Ala missense NC_000002.12:g.203867991A>G NC_000002.11:g.204732714A>G NG_011502.1:g.5206A>G LRG_1220:g.5206A>G LRG_1220t1:c.49A>G LRG_1220p1:p.Thr17Ala P16410:p.Thr17Ala - Protein change
- T17A
- Other names
- CTLA4, 49A-G, THR17ALA
- Canonical SPDI
- NC_000002.12:203867990:A:G
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
0.42732 (G)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.39355
The Genome Aggregation Database (gnomAD) 0.39951
1000 Genomes Project 30x 0.42473
1000 Genomes Project 0.42732
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. |
|||
CTLA4 | - | - |
GRCh38 GRCh37 |
222 | 271 |
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. |
---|---|---|---|---|
risk factor (1) |
no assertion criteria provided
|
Apr 1, 2005 | RCV000018427.5 | |
risk factor (1) |
no assertion criteria provided
|
Apr 1, 2005 | RCV000018423.5 | |
risk factor (1) |
no assertion criteria provided
|
Apr 1, 2005 | RCV000018425.5 | |
risk factor (1) |
no assertion criteria provided
|
Apr 1, 2005 | RCV000018424.5 | |
Benign (1) |
criteria provided, single submitter
|
Mar 29, 2016 | RCV000455037.4 | |
risk factor (1) |
no assertion criteria provided
|
Apr 1, 2005 | RCV001255201.1 | |
Benign (1) |
criteria provided, single submitter
|
Feb 1, 2024 | RCV001517779.6 | |
Benign (2) |
criteria provided, single submitter
|
Nov 10, 2018 | RCV001723578.3 |
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. |
|
---|---|---|---|---|---|
Benign
(Nov 10, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001950680.2
First in ClinVar: Oct 02, 2021 Last updated: Mar 04, 2023 |
Comment:
This variant is associated with the following publications: (PMID: 19737153, 19037649, 22497911, 20920330, 21387262, 18757416, 23830732, 21503616, 21612409, 22011251, 19884265, 20145677, 11426323, 21453059, 22905924, 20538028, … (more)
This variant is associated with the following publications: (PMID: 19737153, 19037649, 22497911, 20920330, 21387262, 18757416, 23830732, 21503616, 21612409, 22011251, 19884265, 20145677, 11426323, 21453059, 22905924, 20538028, 23246583, 19922464, 11976786, 12417883, 22699762, 21346773, 21629267, 20940051, 9259273, 24517008, 28220572) (less)
|
|
Benign
(Mar 29, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000538749.1
First in ClinVar: Apr 09, 2017 Last updated: Apr 09, 2017 |
Comment:
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or … (more)
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: MAF (less)
Method: Genome/Exome Filtration
|
|
Benign
(Feb 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsuffiency
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV001726347.4
First in ClinVar: Jun 15, 2021 Last updated: Feb 20, 2024 |
|
|
risk factor
(Apr 01, 2005)
|
no assertion criteria provided
Method: literature only
|
THYROID-ASSOCIATED ORBITOPATHY, SUSCEPTIBILITY TO
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000038706.4
First in ClinVar: Apr 04, 2013 Last updated: Sep 14, 2020 |
Comment on evidence:
Nistico et al. (1996) identified a 49A-G transition polymorphism in exon 1 of the CTLA4 gene, resulting in a thr17-to-ala (T17A) substitution. Among 529 Belgian … (more)
Nistico et al. (1996) identified a 49A-G transition polymorphism in exon 1 of the CTLA4 gene, resulting in a thr17-to-ala (T17A) substitution. Among 529 Belgian control individuals, the frequencies for the 49A and 49G alleles were 68% and 32%, respectively. In 48 Italian families in which at least 2 sibs were affected with type 1 diabetes mellitus (T1D12; 601388), Nistico et al. (1996) found evidence for preferential transmission of the 49G allele to affected offspring. Similar findings were obtained for 44 Spanish IDDM families, but not for families from the United Kingdom, Sardinia, or the US. Marron et al. (1997) found highly significant transmission of the 49G allele in patients with IDDM in 3 Mediterranean European populations (Italian, Spanish, and French), a Mexican American population, and Korean population. However, significant heterogeneity was observed; datasets of British, Sardinian, and Chinese populations did not show any deviation for the A/G polymorphism, whereas the Caucasian American dataset showed a weak transmission deviation. The results suggested that a true IDDM susceptibility locus is located near CTLA4. Donner et al. (1997) found that patients with Hashimoto thyroiditis (140300) had a significantly higher number of the 49G allele compared to controls, both as homozygotes (22% vs 15%) and heterozygotes (53% vs 46%), and less of the A allele compared to controls as homozygotes (25% vs 39%; P less than 0.04). They also found that the phenotypic frequency for the G allele was significantly higher in patients (75%), compared with controls (61%), P less than 0.03. Whereas Addison disease (240200) subjects did not differ significantly from controls, those carrying the susceptibility marker, human leukocyte antigen DQA1*0501, had a significantly higher frequency of the G allele than controls with the same DQA1 allele (P less than 0.05). Donner et al. (1997) concluded that the 49G allele (ala17) of the CTLA4 gene conferred genetic susceptibility to Hashimoto thyroiditis, whereas this finding only applied to the subgroup of patients with Addison disease carrying DQA1*0501+. Vaidya et al. (1999) presented evidence that the alanine-17 allele also confers susceptibility to thyroid-associated orbitopathy in patients with Graves disease. Rau et al. (2001) analyzed the CTLA4 49A/G polymorphism in 300 Caucasian patients with type 2 diabetes (125853) and 466 healthy controls. All patients were negative for glutamate decarboxylase and islet cell antibodies. The distribution of alleles and the genotypic and phenotypic frequencies were similar among patients and controls. However, analysis of clinical and biochemical parameters revealed a tendency of GG (alanine/alanine) toward younger age at disease manifestation, lower body mass index, and basal C-peptide level, as well as earlier start of insulin treatment and higher portion of patients on insulin. Patients with the AA genotype were significantly less likely to develop microangiopathic lesions. The authors concluded that CTLA4 ala17 does not represent a major risk factor for type II diabetes. Zalloua et al. (2004) evaluated the role of the CTLA4 exon 1 A49G polymorphism as a risk factor for type 1 diabetes in the Lebanese population. The CTLA4 G allele was found to be more frequently present in patients with type 1 diabetes (32.4%) than in control individuals (24.5%). The GG genotype was also significantly higher among patients (12.6%) than in controls (4.2%). Furthermore, in HLA-DQB1*0201-positive patients with type 1 diabetes, the GG and AA genotypes were higher and lower, respectively, than those found in control individuals. In a metaanalysis of 7 published studies and their own study, Barreto et al. (2004) examined the association between the 49A-G SNP and systemic lupus erythematosus (152700). The authors found that individuals with the GG genotype were at significantly higher risk of developing SLE; carriers of the A allele had a significantly lower risk of developing the disease, and the AA genotype acted as a protective genotype for SLE. In a metaanalysis of 14 independent studies testing association between CTLA4 polymorphisms and SLE, Lee et al. (2005) confirmed that the 49A-G polymorphism is significantly associated with SLE susceptibility, particularly in Asians. Djilali-Saiah et al. (1998) found a significantly increased frequency of the 49A allele in 101 French Caucasian patients with celiac disease compared to controls (82.2% vs 65.8%, p less than 0.0001), reflecting the increased frequency of A/A homozygotes among patients compared with controls (68.3% vs 47.7%, p = 0.002). The effect remained after stratification of patients according to their DR-DQ phenotype. The authors concluded that the A allele of the CTLA4 position 49 polymorphism conferred an HLA-independent predisposition to celiac disease. Naluai et al. (2000) analyzed the 49A/G polymorphism in 107 Swedish and Norwegian families with celiac disease and found a significant association, with preferential transmission of the 49A allele by the transmission disequilibrium test (p less than 0.007). Nonparametric linkage analysis yielded a score of 2.1 (p = 0.018), suggesting that the CTLA4 region is a susceptibility region in celiac disease. Naluai et al. (2000) noted that, of several chronic inflammatory diseases exhibiting associations to the CTLA4 49A/G polymorphism, celiac disease is the only one associated with the A allele, suggesting that the 49A/G alleles of CTLA4 are in linkage disequilibrium with 2 distinct disease-predisposing alleles with separate effects. (less)
|
|
risk factor
(Apr 01, 2005)
|
no assertion criteria provided
Method: literature only
|
SYSTEMIC LUPUS ERYTHEMATOSUS, SUSCEPTIBILITY TO
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000038707.4
First in ClinVar: Apr 04, 2013 Last updated: Sep 14, 2020 |
Comment on evidence:
Nistico et al. (1996) identified a 49A-G transition polymorphism in exon 1 of the CTLA4 gene, resulting in a thr17-to-ala (T17A) substitution. Among 529 Belgian … (more)
Nistico et al. (1996) identified a 49A-G transition polymorphism in exon 1 of the CTLA4 gene, resulting in a thr17-to-ala (T17A) substitution. Among 529 Belgian control individuals, the frequencies for the 49A and 49G alleles were 68% and 32%, respectively. In 48 Italian families in which at least 2 sibs were affected with type 1 diabetes mellitus (T1D12; 601388), Nistico et al. (1996) found evidence for preferential transmission of the 49G allele to affected offspring. Similar findings were obtained for 44 Spanish IDDM families, but not for families from the United Kingdom, Sardinia, or the US. Marron et al. (1997) found highly significant transmission of the 49G allele in patients with IDDM in 3 Mediterranean European populations (Italian, Spanish, and French), a Mexican American population, and Korean population. However, significant heterogeneity was observed; datasets of British, Sardinian, and Chinese populations did not show any deviation for the A/G polymorphism, whereas the Caucasian American dataset showed a weak transmission deviation. The results suggested that a true IDDM susceptibility locus is located near CTLA4. Donner et al. (1997) found that patients with Hashimoto thyroiditis (140300) had a significantly higher number of the 49G allele compared to controls, both as homozygotes (22% vs 15%) and heterozygotes (53% vs 46%), and less of the A allele compared to controls as homozygotes (25% vs 39%; P less than 0.04). They also found that the phenotypic frequency for the G allele was significantly higher in patients (75%), compared with controls (61%), P less than 0.03. Whereas Addison disease (240200) subjects did not differ significantly from controls, those carrying the susceptibility marker, human leukocyte antigen DQA1*0501, had a significantly higher frequency of the G allele than controls with the same DQA1 allele (P less than 0.05). Donner et al. (1997) concluded that the 49G allele (ala17) of the CTLA4 gene conferred genetic susceptibility to Hashimoto thyroiditis, whereas this finding only applied to the subgroup of patients with Addison disease carrying DQA1*0501+. Vaidya et al. (1999) presented evidence that the alanine-17 allele also confers susceptibility to thyroid-associated orbitopathy in patients with Graves disease. Rau et al. (2001) analyzed the CTLA4 49A/G polymorphism in 300 Caucasian patients with type 2 diabetes (125853) and 466 healthy controls. All patients were negative for glutamate decarboxylase and islet cell antibodies. The distribution of alleles and the genotypic and phenotypic frequencies were similar among patients and controls. However, analysis of clinical and biochemical parameters revealed a tendency of GG (alanine/alanine) toward younger age at disease manifestation, lower body mass index, and basal C-peptide level, as well as earlier start of insulin treatment and higher portion of patients on insulin. Patients with the AA genotype were significantly less likely to develop microangiopathic lesions. The authors concluded that CTLA4 ala17 does not represent a major risk factor for type II diabetes. Zalloua et al. (2004) evaluated the role of the CTLA4 exon 1 A49G polymorphism as a risk factor for type 1 diabetes in the Lebanese population. The CTLA4 G allele was found to be more frequently present in patients with type 1 diabetes (32.4%) than in control individuals (24.5%). The GG genotype was also significantly higher among patients (12.6%) than in controls (4.2%). Furthermore, in HLA-DQB1*0201-positive patients with type 1 diabetes, the GG and AA genotypes were higher and lower, respectively, than those found in control individuals. In a metaanalysis of 7 published studies and their own study, Barreto et al. (2004) examined the association between the 49A-G SNP and systemic lupus erythematosus (152700). The authors found that individuals with the GG genotype were at significantly higher risk of developing SLE; carriers of the A allele had a significantly lower risk of developing the disease, and the AA genotype acted as a protective genotype for SLE. In a metaanalysis of 14 independent studies testing association between CTLA4 polymorphisms and SLE, Lee et al. (2005) confirmed that the 49A-G polymorphism is significantly associated with SLE susceptibility, particularly in Asians. Djilali-Saiah et al. (1998) found a significantly increased frequency of the 49A allele in 101 French Caucasian patients with celiac disease compared to controls (82.2% vs 65.8%, p less than 0.0001), reflecting the increased frequency of A/A homozygotes among patients compared with controls (68.3% vs 47.7%, p = 0.002). The effect remained after stratification of patients according to their DR-DQ phenotype. The authors concluded that the A allele of the CTLA4 position 49 polymorphism conferred an HLA-independent predisposition to celiac disease. Naluai et al. (2000) analyzed the 49A/G polymorphism in 107 Swedish and Norwegian families with celiac disease and found a significant association, with preferential transmission of the 49A allele by the transmission disequilibrium test (p less than 0.007). Nonparametric linkage analysis yielded a score of 2.1 (p = 0.018), suggesting that the CTLA4 region is a susceptibility region in celiac disease. Naluai et al. (2000) noted that, of several chronic inflammatory diseases exhibiting associations to the CTLA4 49A/G polymorphism, celiac disease is the only one associated with the A allele, suggesting that the 49A/G alleles of CTLA4 are in linkage disequilibrium with 2 distinct disease-predisposing alleles with separate effects. (less)
|
|
risk factor
(Apr 01, 2005)
|
no assertion criteria provided
Method: literature only
|
TYPE 1 DIABETES MELLITUS 12, SUSCEPTIBILITY TO
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV001431556.1
First in ClinVar: Sep 14, 2020 Last updated: Sep 14, 2020 |
Comment on evidence:
Nistico et al. (1996) identified a 49A-G transition polymorphism in exon 1 of the CTLA4 gene, resulting in a thr17-to-ala (T17A) substitution. Among 529 Belgian … (more)
Nistico et al. (1996) identified a 49A-G transition polymorphism in exon 1 of the CTLA4 gene, resulting in a thr17-to-ala (T17A) substitution. Among 529 Belgian control individuals, the frequencies for the 49A and 49G alleles were 68% and 32%, respectively. In 48 Italian families in which at least 2 sibs were affected with type 1 diabetes mellitus (T1D12; 601388), Nistico et al. (1996) found evidence for preferential transmission of the 49G allele to affected offspring. Similar findings were obtained for 44 Spanish IDDM families, but not for families from the United Kingdom, Sardinia, or the US. Marron et al. (1997) found highly significant transmission of the 49G allele in patients with IDDM in 3 Mediterranean European populations (Italian, Spanish, and French), a Mexican American population, and Korean population. However, significant heterogeneity was observed; datasets of British, Sardinian, and Chinese populations did not show any deviation for the A/G polymorphism, whereas the Caucasian American dataset showed a weak transmission deviation. The results suggested that a true IDDM susceptibility locus is located near CTLA4. Donner et al. (1997) found that patients with Hashimoto thyroiditis (140300) had a significantly higher number of the 49G allele compared to controls, both as homozygotes (22% vs 15%) and heterozygotes (53% vs 46%), and less of the A allele compared to controls as homozygotes (25% vs 39%; P less than 0.04). They also found that the phenotypic frequency for the G allele was significantly higher in patients (75%), compared with controls (61%), P less than 0.03. Whereas Addison disease (240200) subjects did not differ significantly from controls, those carrying the susceptibility marker, human leukocyte antigen DQA1*0501, had a significantly higher frequency of the G allele than controls with the same DQA1 allele (P less than 0.05). Donner et al. (1997) concluded that the 49G allele (ala17) of the CTLA4 gene conferred genetic susceptibility to Hashimoto thyroiditis, whereas this finding only applied to the subgroup of patients with Addison disease carrying DQA1*0501+. Vaidya et al. (1999) presented evidence that the alanine-17 allele also confers susceptibility to thyroid-associated orbitopathy in patients with Graves disease. Rau et al. (2001) analyzed the CTLA4 49A/G polymorphism in 300 Caucasian patients with type 2 diabetes (125853) and 466 healthy controls. All patients were negative for glutamate decarboxylase and islet cell antibodies. The distribution of alleles and the genotypic and phenotypic frequencies were similar among patients and controls. However, analysis of clinical and biochemical parameters revealed a tendency of GG (alanine/alanine) toward younger age at disease manifestation, lower body mass index, and basal C-peptide level, as well as earlier start of insulin treatment and higher portion of patients on insulin. Patients with the AA genotype were significantly less likely to develop microangiopathic lesions. The authors concluded that CTLA4 ala17 does not represent a major risk factor for type II diabetes. Zalloua et al. (2004) evaluated the role of the CTLA4 exon 1 A49G polymorphism as a risk factor for type 1 diabetes in the Lebanese population. The CTLA4 G allele was found to be more frequently present in patients with type 1 diabetes (32.4%) than in control individuals (24.5%). The GG genotype was also significantly higher among patients (12.6%) than in controls (4.2%). Furthermore, in HLA-DQB1*0201-positive patients with type 1 diabetes, the GG and AA genotypes were higher and lower, respectively, than those found in control individuals. In a metaanalysis of 7 published studies and their own study, Barreto et al. (2004) examined the association between the 49A-G SNP and systemic lupus erythematosus (152700). The authors found that individuals with the GG genotype were at significantly higher risk of developing SLE; carriers of the A allele had a significantly lower risk of developing the disease, and the AA genotype acted as a protective genotype for SLE. In a metaanalysis of 14 independent studies testing association between CTLA4 polymorphisms and SLE, Lee et al. (2005) confirmed that the 49A-G polymorphism is significantly associated with SLE susceptibility, particularly in Asians. Djilali-Saiah et al. (1998) found a significantly increased frequency of the 49A allele in 101 French Caucasian patients with celiac disease compared to controls (82.2% vs 65.8%, p less than 0.0001), reflecting the increased frequency of A/A homozygotes among patients compared with controls (68.3% vs 47.7%, p = 0.002). The effect remained after stratification of patients according to their DR-DQ phenotype. The authors concluded that the A allele of the CTLA4 position 49 polymorphism conferred an HLA-independent predisposition to celiac disease. Naluai et al. (2000) analyzed the 49A/G polymorphism in 107 Swedish and Norwegian families with celiac disease and found a significant association, with preferential transmission of the 49A allele by the transmission disequilibrium test (p less than 0.007). Nonparametric linkage analysis yielded a score of 2.1 (p = 0.018), suggesting that the CTLA4 region is a susceptibility region in celiac disease. Naluai et al. (2000) noted that, of several chronic inflammatory diseases exhibiting associations to the CTLA4 49A/G polymorphism, celiac disease is the only one associated with the A allele, suggesting that the 49A/G alleles of CTLA4 are in linkage disequilibrium with 2 distinct disease-predisposing alleles with separate effects. (less)
|
|
risk factor
(Apr 01, 2005)
|
no assertion criteria provided
Method: literature only
|
CELIAC DISEASE, SUSCEPTIBILITY TO, 3
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000038709.4
First in ClinVar: Apr 04, 2013 Last updated: Sep 14, 2020 |
Comment on evidence:
Nistico et al. (1996) identified a 49A-G transition polymorphism in exon 1 of the CTLA4 gene, resulting in a thr17-to-ala (T17A) substitution. Among 529 Belgian … (more)
Nistico et al. (1996) identified a 49A-G transition polymorphism in exon 1 of the CTLA4 gene, resulting in a thr17-to-ala (T17A) substitution. Among 529 Belgian control individuals, the frequencies for the 49A and 49G alleles were 68% and 32%, respectively. In 48 Italian families in which at least 2 sibs were affected with type 1 diabetes mellitus (T1D12; 601388), Nistico et al. (1996) found evidence for preferential transmission of the 49G allele to affected offspring. Similar findings were obtained for 44 Spanish IDDM families, but not for families from the United Kingdom, Sardinia, or the US. Marron et al. (1997) found highly significant transmission of the 49G allele in patients with IDDM in 3 Mediterranean European populations (Italian, Spanish, and French), a Mexican American population, and Korean population. However, significant heterogeneity was observed; datasets of British, Sardinian, and Chinese populations did not show any deviation for the A/G polymorphism, whereas the Caucasian American dataset showed a weak transmission deviation. The results suggested that a true IDDM susceptibility locus is located near CTLA4. Donner et al. (1997) found that patients with Hashimoto thyroiditis (140300) had a significantly higher number of the 49G allele compared to controls, both as homozygotes (22% vs 15%) and heterozygotes (53% vs 46%), and less of the A allele compared to controls as homozygotes (25% vs 39%; P less than 0.04). They also found that the phenotypic frequency for the G allele was significantly higher in patients (75%), compared with controls (61%), P less than 0.03. Whereas Addison disease (240200) subjects did not differ significantly from controls, those carrying the susceptibility marker, human leukocyte antigen DQA1*0501, had a significantly higher frequency of the G allele than controls with the same DQA1 allele (P less than 0.05). Donner et al. (1997) concluded that the 49G allele (ala17) of the CTLA4 gene conferred genetic susceptibility to Hashimoto thyroiditis, whereas this finding only applied to the subgroup of patients with Addison disease carrying DQA1*0501+. Vaidya et al. (1999) presented evidence that the alanine-17 allele also confers susceptibility to thyroid-associated orbitopathy in patients with Graves disease. Rau et al. (2001) analyzed the CTLA4 49A/G polymorphism in 300 Caucasian patients with type 2 diabetes (125853) and 466 healthy controls. All patients were negative for glutamate decarboxylase and islet cell antibodies. The distribution of alleles and the genotypic and phenotypic frequencies were similar among patients and controls. However, analysis of clinical and biochemical parameters revealed a tendency of GG (alanine/alanine) toward younger age at disease manifestation, lower body mass index, and basal C-peptide level, as well as earlier start of insulin treatment and higher portion of patients on insulin. Patients with the AA genotype were significantly less likely to develop microangiopathic lesions. The authors concluded that CTLA4 ala17 does not represent a major risk factor for type II diabetes. Zalloua et al. (2004) evaluated the role of the CTLA4 exon 1 A49G polymorphism as a risk factor for type 1 diabetes in the Lebanese population. The CTLA4 G allele was found to be more frequently present in patients with type 1 diabetes (32.4%) than in control individuals (24.5%). The GG genotype was also significantly higher among patients (12.6%) than in controls (4.2%). Furthermore, in HLA-DQB1*0201-positive patients with type 1 diabetes, the GG and AA genotypes were higher and lower, respectively, than those found in control individuals. In a metaanalysis of 7 published studies and their own study, Barreto et al. (2004) examined the association between the 49A-G SNP and systemic lupus erythematosus (152700). The authors found that individuals with the GG genotype were at significantly higher risk of developing SLE; carriers of the A allele had a significantly lower risk of developing the disease, and the AA genotype acted as a protective genotype for SLE. In a metaanalysis of 14 independent studies testing association between CTLA4 polymorphisms and SLE, Lee et al. (2005) confirmed that the 49A-G polymorphism is significantly associated with SLE susceptibility, particularly in Asians. Djilali-Saiah et al. (1998) found a significantly increased frequency of the 49A allele in 101 French Caucasian patients with celiac disease compared to controls (82.2% vs 65.8%, p less than 0.0001), reflecting the increased frequency of A/A homozygotes among patients compared with controls (68.3% vs 47.7%, p = 0.002). The effect remained after stratification of patients according to their DR-DQ phenotype. The authors concluded that the A allele of the CTLA4 position 49 polymorphism conferred an HLA-independent predisposition to celiac disease. Naluai et al. (2000) analyzed the 49A/G polymorphism in 107 Swedish and Norwegian families with celiac disease and found a significant association, with preferential transmission of the 49A allele by the transmission disequilibrium test (p less than 0.007). Nonparametric linkage analysis yielded a score of 2.1 (p = 0.018), suggesting that the CTLA4 region is a susceptibility region in celiac disease. Naluai et al. (2000) noted that, of several chronic inflammatory diseases exhibiting associations to the CTLA4 49A/G polymorphism, celiac disease is the only one associated with the A allele, suggesting that the 49A/G alleles of CTLA4 are in linkage disequilibrium with 2 distinct disease-predisposing alleles with separate effects. (less)
|
|
risk factor
(Apr 01, 2005)
|
no assertion criteria provided
Method: literature only
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HASHIMOTO THYROIDITIS, SUSCEPTIBILITY TO
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000038705.4
First in ClinVar: Apr 04, 2013 Last updated: Sep 14, 2020 |
Comment on evidence:
Nistico et al. (1996) identified a 49A-G transition polymorphism in exon 1 of the CTLA4 gene, resulting in a thr17-to-ala (T17A) substitution. Among 529 Belgian … (more)
Nistico et al. (1996) identified a 49A-G transition polymorphism in exon 1 of the CTLA4 gene, resulting in a thr17-to-ala (T17A) substitution. Among 529 Belgian control individuals, the frequencies for the 49A and 49G alleles were 68% and 32%, respectively. In 48 Italian families in which at least 2 sibs were affected with type 1 diabetes mellitus (T1D12; 601388), Nistico et al. (1996) found evidence for preferential transmission of the 49G allele to affected offspring. Similar findings were obtained for 44 Spanish IDDM families, but not for families from the United Kingdom, Sardinia, or the US. Marron et al. (1997) found highly significant transmission of the 49G allele in patients with IDDM in 3 Mediterranean European populations (Italian, Spanish, and French), a Mexican American population, and Korean population. However, significant heterogeneity was observed; datasets of British, Sardinian, and Chinese populations did not show any deviation for the A/G polymorphism, whereas the Caucasian American dataset showed a weak transmission deviation. The results suggested that a true IDDM susceptibility locus is located near CTLA4. Donner et al. (1997) found that patients with Hashimoto thyroiditis (140300) had a significantly higher number of the 49G allele compared to controls, both as homozygotes (22% vs 15%) and heterozygotes (53% vs 46%), and less of the A allele compared to controls as homozygotes (25% vs 39%; P less than 0.04). They also found that the phenotypic frequency for the G allele was significantly higher in patients (75%), compared with controls (61%), P less than 0.03. Whereas Addison disease (240200) subjects did not differ significantly from controls, those carrying the susceptibility marker, human leukocyte antigen DQA1*0501, had a significantly higher frequency of the G allele than controls with the same DQA1 allele (P less than 0.05). Donner et al. (1997) concluded that the 49G allele (ala17) of the CTLA4 gene conferred genetic susceptibility to Hashimoto thyroiditis, whereas this finding only applied to the subgroup of patients with Addison disease carrying DQA1*0501+. Vaidya et al. (1999) presented evidence that the alanine-17 allele also confers susceptibility to thyroid-associated orbitopathy in patients with Graves disease. Rau et al. (2001) analyzed the CTLA4 49A/G polymorphism in 300 Caucasian patients with type 2 diabetes (125853) and 466 healthy controls. All patients were negative for glutamate decarboxylase and islet cell antibodies. The distribution of alleles and the genotypic and phenotypic frequencies were similar among patients and controls. However, analysis of clinical and biochemical parameters revealed a tendency of GG (alanine/alanine) toward younger age at disease manifestation, lower body mass index, and basal C-peptide level, as well as earlier start of insulin treatment and higher portion of patients on insulin. Patients with the AA genotype were significantly less likely to develop microangiopathic lesions. The authors concluded that CTLA4 ala17 does not represent a major risk factor for type II diabetes. Zalloua et al. (2004) evaluated the role of the CTLA4 exon 1 A49G polymorphism as a risk factor for type 1 diabetes in the Lebanese population. The CTLA4 G allele was found to be more frequently present in patients with type 1 diabetes (32.4%) than in control individuals (24.5%). The GG genotype was also significantly higher among patients (12.6%) than in controls (4.2%). Furthermore, in HLA-DQB1*0201-positive patients with type 1 diabetes, the GG and AA genotypes were higher and lower, respectively, than those found in control individuals. In a metaanalysis of 7 published studies and their own study, Barreto et al. (2004) examined the association between the 49A-G SNP and systemic lupus erythematosus (152700). The authors found that individuals with the GG genotype were at significantly higher risk of developing SLE; carriers of the A allele had a significantly lower risk of developing the disease, and the AA genotype acted as a protective genotype for SLE. In a metaanalysis of 14 independent studies testing association between CTLA4 polymorphisms and SLE, Lee et al. (2005) confirmed that the 49A-G polymorphism is significantly associated with SLE susceptibility, particularly in Asians. Djilali-Saiah et al. (1998) found a significantly increased frequency of the 49A allele in 101 French Caucasian patients with celiac disease compared to controls (82.2% vs 65.8%, p less than 0.0001), reflecting the increased frequency of A/A homozygotes among patients compared with controls (68.3% vs 47.7%, p = 0.002). The effect remained after stratification of patients according to their DR-DQ phenotype. The authors concluded that the A allele of the CTLA4 position 49 polymorphism conferred an HLA-independent predisposition to celiac disease. Naluai et al. (2000) analyzed the 49A/G polymorphism in 107 Swedish and Norwegian families with celiac disease and found a significant association, with preferential transmission of the 49A allele by the transmission disequilibrium test (p less than 0.007). Nonparametric linkage analysis yielded a score of 2.1 (p = 0.018), suggesting that the CTLA4 region is a susceptibility region in celiac disease. Naluai et al. (2000) noted that, of several chronic inflammatory diseases exhibiting associations to the CTLA4 49A/G polymorphism, celiac disease is the only one associated with the A allele, suggesting that the 49A/G alleles of CTLA4 are in linkage disequilibrium with 2 distinct disease-predisposing alleles with separate effects. (less)
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not provided
(-)
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no classification provided
Method: phenotyping only
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Not Provided
Affected status: unknown
Allele origin:
unknown
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GenomeConnect, ClinGen
Accession: SCV002074600.1
First in ClinVar: Feb 11, 2022 Last updated: Feb 11, 2022 |
Comment:
Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided … (more)
Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. (less)
Clinical Features:
Phenotypic abnormality (present)
Indication for testing: Diagnostic
Age: 40-49 years
Sex: female
Testing laboratory: Invitae
Date variant was reported to submitter: 2020-04-27
Testing laboratory interpretation: Benign
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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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CTLA-4 polymorphisms and systemic lupus erythematosus (SLE): a meta-analysis. | Lee YH | Human genetics | 2005 | PMID: 15688186 |
Patients with early onset of type 1 diabetes have significantly higher GG genotype at position 49 of the CTLA4 gene. | Zalloua PA | Human immunology | 2004 | PMID: 15301861 |
Evidence for CTLA4 as a susceptibility gene for systemic lupus erythematosus. | Barreto M | European journal of human genetics : EJHG | 2004 | PMID: 15138458 |
The codon 17 polymorphism of the CTLA4 gene in type 2 diabetes mellitus. | Rau H | The Journal of clinical endocrinology and metabolism | 2001 | PMID: 11158025 |
The CTLA4/CD28 gene region on chromosome 2q33 confers susceptibility to celiac disease in a way possibly distinct from that of type 1 diabetes and other chronic inflammatory disorders. | Naluai AT | Tissue antigens | 2000 | PMID: 11098935 |
Cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphism confers susceptibility to thyroid associated orbitopathy. | Vaidya B | Lancet (London, England) | 1999 | PMID: 10475192 |
CTLA-4 gene polymorphism is associated with predisposition to coeliac disease. | Djilali-Saiah I | Gut | 1998 | PMID: 10189842 |
Codon 17 polymorphism of the cytotoxic T lymphocyte antigen 4 gene in Hashimoto's thyroiditis and Addison's disease. | Donner H | The Journal of clinical endocrinology and metabolism | 1997 | PMID: 9398726 |
Insulin-dependent diabetes mellitus (IDDM) is associated with CTLA4 polymorphisms in multiple ethnic groups. | Marron MP | Human molecular genetics | 1997 | PMID: 9259273 |
The CTLA-4 gene region of chromosome 2q33 is linked to, and associated with, type 1 diabetes. Belgian Diabetes Registry. | Nisticò L | Human molecular genetics | 1996 | PMID: 8817351 |
Text-mined citations for rs231775 ...
HelpRecord last updated Feb 28, 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.