The c.1265delC; p.Pro422LeufsTer58 variant has been reported previously in a patient with autoimmune polyendocrinopathy syndrome type 1 (AIRE); however, no additional variant was identified in that patient (Heino et al., 1999). The deletion causes a frameshift starting with codon Proline 422, changes this amino acid to a Leucine residue and creates a premature Stop codon at position 58 of the new reading frame, denoted p.Pro422LeufsX58. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Therefore, we consider this variant to be pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000383.4(AIRE):c.1265del (p.Pro422fs)
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.
(8)
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
8
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000383.4(AIRE):c.1265del (p.Pro422fs)
Variation ID: 265456 Accession: VCV000265456.13
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 21q22.3 21: 44293161 (GRCh38) [ NCBI UCSC ] 21: 45713044 (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 10, 2016 Feb 14, 2024 Oct 23, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000383.4:c.1265del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000374.1:p.Pro422fs frameshift NM_000383.2:c.1265delC NM_000383.3:c.1265del NC_000021.9:g.44293162del NC_000021.8:g.45713045del NG_009556.1:g.12283del LRG_18:g.12283del LRG_18t1:c.1265del - Protein change
- P422fs
- Other names
- -
- Canonical SPDI
- NC_000021.9:44293160:CC:C
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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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- 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. |
|||
| AIRE | - | - |
GRCh38 GRCh37 |
1134 | 1275 | |
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 (2) |
criteria provided, multiple submitters, no conflicts
|
Mar 27, 2018 | RCV000255362.5 | |
| Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Oct 23, 2023 | RCV000515133.11 |
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
(Oct 31, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Polyglandular autoimmune syndrome, type 1
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV000609491.1
First in ClinVar: Nov 08, 2017 Last updated: Nov 08, 2017 |
Comment:
The c.1265delC; p.Pro422LeufsTer58 variant has been reported previously in a patient with autoimmune polyendocrinopathy syndrome type 1 (AIRE); however, no additional variant was identified in … (more)
The c.1265delC; p.Pro422LeufsTer58 variant has been reported previously in a patient with autoimmune polyendocrinopathy syndrome type 1 (AIRE); however, no additional variant was identified in that patient (Heino et al., 1999). The deletion causes a frameshift starting with codon Proline 422, changes this amino acid to a Leucine residue and creates a premature Stop codon at position 58 of the new reading frame, denoted p.Pro422LeufsX58. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Therefore, we consider this variant to be pathogenic. (less)
|
|
|
Pathogenic
(Aug 04, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000322390.7
First in ClinVar: Oct 10, 2016 Last updated: Oct 28, 2018 |
Comment:
The c.1265delC pathogenic variant in the AIRE gene has been reported previously in a patient with autoimmune polyendocrinopathy syndrome type 1; however, no additional variant … (more)
The c.1265delC pathogenic variant in the AIRE gene has been reported previously in a patient with autoimmune polyendocrinopathy syndrome type 1; however, no additional variant was identified in that patient (Heino et al., 1999). The deletion causes a frameshift starting with codon Proline 422, changes this amino acid to a Leucine residue and creates a premature Stop codon at position 58 of the new reading frame, denoted p.Pro422LeufsX58. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Therefore, we consider this variant to be pathogenic. (less)
|
|
|
Pathogenic
(Mar 27, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Athena Diagnostics
Accession: SCV000840727.1
First in ClinVar: Oct 20, 2018 Last updated: Oct 20, 2018 |
|
|
|
Pathogenic
(Oct 24, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Polyglandular autoimmune syndrome, type 1
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001361216.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: AIRE c.1265delC (p.Pro422LeufsX58) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: AIRE c.1265delC (p.Pro422LeufsX58) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 2.2e-05 in 184258 control chromosomes (gnomAD). c.1265delC has been reported in the literature in individuals affected with Autoimmune Polyglandular Syndrome Type 1 (Heino_1999, Pearce_1998, Sanford_2018). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(May 19, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Polyglandular autoimmune syndrome, type 1
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002810356.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Sep 14, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
APECED
Affected status: yes
Allele origin:
germline
|
National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health
Accession: SCV004036177.1
First in ClinVar: Sep 30, 2023 Last updated: Sep 30, 2023 |
|
|
|
Pathogenic
(Oct 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Polyglandular autoimmune syndrome, type 1
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001587734.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Pro422Leufs*58) in the AIRE gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Pro422Leufs*58) in the AIRE gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AIRE are known to be pathogenic (PMID: 11524731, 26141571). This variant is present in population databases (rs764878471, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with autosomal recessive autoimmune polyendocrinopathy syndrome (PMID: 9888391, 29437776). ClinVar contains an entry for this variant (Variation ID: 265456). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Likely pathogenic
(Jul 17, 2015)
|
no assertion criteria provided
Method: clinical testing
|
Polyglandular autoimmune syndrome, type 1
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV001132331.1
First in ClinVar: Dec 23, 2019 Last updated: Dec 23, 2019 |
|
Comment:
Comment:
The c.1265delC pathogenic variant in the AIRE gene has been reported previously in a patient with autoimmune polyendocrinopathy syndrome type 1; however, no additional variant was identified in that patient (Heino et al., 1999). The deletion causes a frameshift starting with codon Proline 422, changes this amino acid to a Leucine residue and creates a premature Stop codon at position 58 of the new reading frame, denoted p.Pro422LeufsX58. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Therefore, we consider this variant to be pathogenic.
Comment:
Variant summary: AIRE c.1265delC (p.Pro422LeufsX58) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 2.2e-05 in 184258 control chromosomes (gnomAD). c.1265delC has been reported in the literature in individuals affected with Autoimmune Polyglandular Syndrome Type 1 (Heino_1999, Pearce_1998, Sanford_2018). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This sequence change creates a premature translational stop signal (p.Pro422Leufs*58) in the AIRE gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AIRE are known to be pathogenic (PMID: 11524731, 26141571). This variant is present in population databases (rs764878471, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with autosomal recessive autoimmune polyendocrinopathy syndrome (PMID: 9888391, 29437776). ClinVar contains an entry for this variant (Variation ID: 265456). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
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. |
Comment:
The c.1265delC; p.Pro422LeufsTer58 variant has been reported previously in a patient with autoimmune polyendocrinopathy syndrome type 1 (AIRE); however, no additional variant was identified in that patient (Heino et al., 1999). The deletion causes a frameshift starting with codon Proline 422, changes this amino acid to a Leucine residue and creates a premature Stop codon at position 58 of the new reading frame, denoted p.Pro422LeufsX58. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Therefore, we consider this variant to be pathogenic.
Comment:
The c.1265delC pathogenic variant in the AIRE gene has been reported previously in a patient with autoimmune polyendocrinopathy syndrome type 1; however, no additional variant was identified in that patient (Heino et al., 1999). The deletion causes a frameshift starting with codon Proline 422, changes this amino acid to a Leucine residue and creates a premature Stop codon at position 58 of the new reading frame, denoted p.Pro422LeufsX58. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Therefore, we consider this variant to be pathogenic.
Comment:
Variant summary: AIRE c.1265delC (p.Pro422LeufsX58) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 2.2e-05 in 184258 control chromosomes (gnomAD). c.1265delC has been reported in the literature in individuals affected with Autoimmune Polyglandular Syndrome Type 1 (Heino_1999, Pearce_1998, Sanford_2018). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This sequence change creates a premature translational stop signal (p.Pro422Leufs*58) in the AIRE gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AIRE are known to be pathogenic (PMID: 11524731, 26141571). This variant is present in population databases (rs764878471, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with autosomal recessive autoimmune polyendocrinopathy syndrome (PMID: 9888391, 29437776). ClinVar contains an entry for this variant (Variation ID: 265456). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Rapid whole-genome sequencing identifies a novel AIRE variant associated with autoimmune polyendocrine syndrome type 1. | Sanford E | Cold Spring Harbor molecular case studies | 2018 | PMID: 29437776 |
| Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy. | Kisand K | Journal of clinical immunology | 2015 | PMID: 26141571 |
| APECED mutations in the autoimmune regulator (AIRE) gene. | Heino M | Human mutation | 2001 | PMID: 11524731 |
| Mutation analyses of North American APS-1 patients. | Heino M | Human mutation | 1999 | PMID: 9888391 |
| A common and recurrent 13-bp deletion in the autoimmune regulator gene in British kindreds with autoimmune polyendocrinopathy type 1. | Pearce SH | American journal of human genetics | 1998 | PMID: 9837820 |
| The importance of creatinine flow, age and 24 h urinary output in the interpretation of the MHPG flow. | Maes M | Journal of affective disorders | 1986 | PMID: 2943776 |
Text-mined citations for rs764878471 ...
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 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.