Normal stop codon changed to a Leucine codon, leading to the addition of 14 amino acids at the C-terminus; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18494745, 20132240, 28321846, 21850189, 25555363, 22204637, 16098226, 6330922, 18494744, 16199712, 22361317, 28698011, 18241071, 10477494, 11309364, 26661695, 12552561, 27431685, 29618921, 29367200, 32360764, 33594928, 27535533, 34101622, 33726816, 32467297)
ClinVar Genomic variation as it relates to human health
NM_001368894.2(PAX6):c.1310A>T (p.Ter437Leu)
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.
(10)
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/Likely pathogenic
10
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001368894.2(PAX6):c.1310A>T (p.Ter437Leu)
Variation ID: 3474 Accession: VCV000003474.48
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p13 11: 31789935 (GRCh38) [ NCBI UCSC ] 11: 31811483 (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 Oct 20, 2024 Jan 1, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001368894.2:c.1310A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001355823.1:p.Ter437Leu stop lost NM_019040.5:c.*6411T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
3 prime UTR NM_000280.6:c.1268A>T NP_000271.1:p.Ter423Leu stop lost NM_001127612.3:c.1268A>T NP_001121084.1:p.Ter423Leu stop lost NM_001258462.3:c.1310A>T NP_001245391.1:p.Ter437Leu stop lost NM_001258463.2:c.1310A>T NP_001245392.1:p.Ter437Leu stop lost NM_001258464.2:c.1268A>T NP_001245393.1:p.Ter423Leu stop lost NM_001258465.3:c.1268A>T NP_001245394.1:p.Ter423Leu stop lost NM_001288725.2:c.*6397T>A 3 prime UTR NM_001288726.2:c.*6506T>A 3 prime UTR NM_001310158.2:c.1310A>T NP_001297087.1:p.Ter437Leu stop lost NM_001310160.2:c.860A>T NP_001297089.1:p.Ter287Leu stop lost NM_001310161.3:c.860A>T NP_001297090.1:p.Ter287Leu stop lost NM_001368887.2:c.1268A>T NP_001355816.1:p.Ter423Leu stop lost NM_001368888.2:c.1268A>T NP_001355817.1:p.Ter423Leu stop lost NM_001368889.2:c.1268A>T NP_001355818.1:p.Ter423Leu stop lost NM_001368890.2:c.1268A>T NP_001355819.1:p.Ter423Leu stop lost NM_001368891.2:c.1268A>T NP_001355820.1:p.Ter423Leu stop lost NM_001368892.2:c.1310A>T NP_001355821.1:p.Ter437Leu stop lost NM_001368893.2:c.1310A>T NP_001355822.1:p.Ter437Leu stop lost NM_001368899.2:c.860A>T NP_001355828.1:p.Ter287Leu stop lost NM_001368900.2:c.860A>T NP_001355829.1:p.Ter287Leu stop lost NM_001368901.2:c.860A>T NP_001355830.1:p.Ter287Leu stop lost NM_001368902.2:c.860A>T NP_001355831.1:p.Ter287Leu stop lost NM_001368903.2:c.860A>T NP_001355832.1:p.Ter287Leu stop lost NM_001368904.2:c.860A>T NP_001355833.1:p.Ter287Leu stop lost NM_001368905.2:c.860A>T NP_001355834.1:p.Ter287Leu stop lost NM_001368906.2:c.860A>T NP_001355835.1:p.Ter287Leu stop lost NM_001368907.2:c.860A>T NP_001355836.1:p.Ter287Leu stop lost NM_001368908.2:c.860A>T NP_001355837.1:p.Ter287Leu stop lost NM_001368909.2:c.860A>T NP_001355838.1:p.Ter287Leu stop lost NM_001368910.2:c.1511A>T NP_001355839.1:p.Ter504Leu stop lost NM_001368911.2:c.1162A>T NP_001355840.1:p.Lys388Ter nonsense NM_001368912.2:c.1159A>T NP_001355841.1:p.Lys387Ter nonsense NM_001368913.2:c.1159A>T NP_001355842.1:p.Lys387Ter nonsense NM_001368914.2:c.1159A>T NP_001355843.1:p.Lys387Ter nonsense NM_001368915.2:c.1117A>T NP_001355844.1:p.Lys373Ter nonsense NM_001368916.2:c.1117A>T NP_001355845.1:p.Lys373Ter nonsense NM_001368917.2:c.1117A>T NP_001355846.1:p.Lys373Ter nonsense NM_001368918.2:c.1385A>T NP_001355847.1:p.Ter462Leu stop lost NM_001368919.2:c.1385A>T NP_001355848.1:p.Ter462Leu stop lost NM_001368920.2:c.1343A>T NP_001355849.1:p.Ter448Leu stop lost NM_001368921.2:c.958A>T NP_001355850.1:p.Lys320Ter nonsense NM_001368922.2:c.1109A>T NP_001355851.1:p.Ter370Leu stop lost NM_001368923.2:c.1109A>T NP_001355852.1:p.Ter370Leu stop lost NM_001368924.2:c.1109A>T NP_001355853.1:p.Ter370Leu stop lost NM_001368925.2:c.1109A>T NP_001355854.1:p.Ter370Leu stop lost NM_001368926.2:c.1109A>T NP_001355855.1:p.Ter370Leu stop lost NM_001368927.2:c.1109A>T NP_001355856.1:p.Ter370Leu stop lost NM_001368928.2:c.1067A>T NP_001355857.1:p.Ter356Leu stop lost NM_001368929.2:c.709A>T NP_001355858.1:p.Lys237Ter nonsense NM_001368930.2:c.665A>T NP_001355859.1:p.Ter222Leu stop lost NM_001604.6:c.1310A>T NP_001595.2:p.Ter437Leu stop lost NR_160916.2:n.1498A>T non-coding transcript variant NR_160917.2:n.1654A>T non-coding transcript variant NC_000011.10:g.31789935T>A NC_000011.9:g.31811483T>A NG_008679.1:g.33027A>T NG_034086.2:g.285170T>A LRG_720:g.33027A>T LRG_720t1:c.1268A>T LRG_720p1:p.Ter423Leu - Protein change
- K387*, K237*, K388*, K320*, K373*
- Other names
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*423L
*437L
*462L
*287L
*222L
*356L
*370L
*448L
*504L
- Canonical SPDI
- NC_000011.10:31789934:T:A
-
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. |
|||
| PAX6 | Sufficient evidence for dosage pathogenicity | Little evidence for dosage pathogenicity |
GRCh38 GRCh37 |
695 | 899 | |
| ELP4 | - | - |
GRCh38 GRCh37 |
62 | 288 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (3) |
criteria provided, single submitter
|
Aug 15, 2019 | RCV000003642.11 | |
| Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Jan 1, 2024 | RCV000327291.31 | |
| no classifications from unflagged records (1) |
no classifications from unflagged records
|
- | RCV000785745.6 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Oct 31, 2018 | RCV000762838.3 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Nov 24, 2023 | RCV000805010.8 |
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
(Jan 15, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000225770.5
First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
|
|
|
Pathogenic
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Aniridia 1
Coloboma, ocular, autosomal dominant Coloboma of optic nerve Foveal hypoplasia 1 Autosomal dominant keratitis Isolated optic nerve hypoplasia 11p partial monosomy syndrome Irido-corneo-trabecular dysgenesis
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000893197.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
|
|
Pathogenic
(Aug 15, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Aniridia 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown,
inherited,
de novo
|
Wessex Regional Genetics Laboratory, Salisbury District Hospital
Accession: SCV001055829.1
First in ClinVar: Dec 23, 2019 Last updated: Dec 23, 2019 |
Observation 1:
Number of individuals with the variant: 1
Observation 2:
Number of individuals with the variant: 1
Observation 3:
Number of individuals with the variant: 1
Observation 4:
Number of individuals with the variant: 1
Observation 5:
Number of individuals with the variant: 1
Observation 6:
Number of individuals with the variant: 1
Observation 7:
Number of individuals with the variant: 1
Observation 8:
Number of individuals with the variant: 1
Observation 9:
Number of individuals with the variant: 1
Observation 10:
Number of individuals with the variant: 1
Observation 11:
Number of individuals with the variant: 1
Observation 12:
Number of individuals with the variant: 1
Observation 13:
Number of individuals with the variant: 1
Observation 14:
Number of individuals with the variant: 1
Observation 15:
Number of individuals with the variant: 1
Observation 16:
Number of individuals with the variant: 1
Observation 17:
Number of individuals with the variant: 1
Observation 18:
Number of individuals with the variant: 1
Observation 19:
Number of individuals with the variant: 1
Observation 20:
Number of individuals with the variant: 1
Observation 21:
Number of individuals with the variant: 1
Observation 22:
Number of individuals with the variant: 1
Observation 23:
Number of individuals with the variant: 1
|
|
|
Likely pathogenic
(Mar 15, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001450012.1
First in ClinVar: Dec 11, 2020 Last updated: Dec 11, 2020 |
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Dec 27, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000329453.8
First in ClinVar: Dec 06, 2016 Last updated: Mar 04, 2023 |
Comment:
Normal stop codon changed to a Leucine codon, leading to the addition of 14 amino acids at the C-terminus; Not observed at significant frequency in … (more)
Normal stop codon changed to a Leucine codon, leading to the addition of 14 amino acids at the C-terminus; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18494745, 20132240, 28321846, 21850189, 25555363, 22204637, 16098226, 6330922, 18494744, 16199712, 22361317, 28698011, 18241071, 10477494, 11309364, 26661695, 12552561, 27431685, 29618921, 29367200, 32360764, 33594928, 27535533, 34101622, 33726816, 32467297) (less)
|
|
|
Pathogenic
(Nov 24, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Aniridia 1
Irido-corneo-trabecular dysgenesis
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000944952.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 28, 2024 |
Comment:
This sequence change disrupts the translational stop signal of the PAX6 mRNA. It is expected to extend the length of the PAX6 protein by 14 … (more)
This sequence change disrupts the translational stop signal of the PAX6 mRNA. It is expected to extend the length of the PAX6 protein by 14 additional amino acid residues. This variant is not present in population databases (gnomAD no frequency). This protein extension has been observed in individual(s) with aniridia (PMID: 11309364, 12552561, 27431685, 28321846, 29618921). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is also known as c.1290 A>T and X437L. ClinVar contains an entry for this variant (Variation ID: 3474). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Jan 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001247619.26
First in ClinVar: May 09, 2020 Last updated: Oct 20, 2024 |
Comment:
PAX6: PP1:Strong, PM2, PM4, PS4:Moderate, PM6:Supporting, PP4
Number of individuals with the variant: 2
|
|
|
Pathogenic
(Feb 01, 2003)
|
no assertion criteria provided
Method: literature only
|
ANIRIDIA
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000023805.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 02, 2016 |
Comment on evidence:
In 7 of 30 patients with aniridia (106210), Chao et al. (2003) found mutation of the normal stop codon 423 in the PAX6 gene from … (more)
In 7 of 30 patients with aniridia (106210), Chao et al. (2003) found mutation of the normal stop codon 423 in the PAX6 gene from TAA (ter) to TTA (leu) (X423L). The change resulted in run-on into the 3-prime UTR. Two of the cases were familial and 5 were sporadic; 1 patient had developmental delay and 'autistic behavior,' and a CT scan showed brain asymmetry. (less)
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: research
|
Aniridia 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Laboratory of Genetic Epidemiology, Research Centre for Medical Genetics
Accession: SCV000584165.1
First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016 |
Geographic origin: Russia
Method: Sanger sequencing
|
|
|
Likely pathogenic
(Mar 29, 2018)
|
Flagged submission
flagged submission
Method: clinical testing
Reason: This record appears to be redundant with a more recent record from the same submitter.
Notes: SCV000924312 appears to be redundant with SCV001450012.
(less)
Notes: SCV000924312 appears to
(...more)
Source: NCBI
|
Nystagmus
Hypertelorism Visual impairment (Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV000924312.1
First in ClinVar: Jun 22, 2019 Last updated: Jun 22, 2019 |
Family history: no
Sex: male
Ethnicity/Population group: Causasians
Tissue: Blood
Secondary finding: no
Method: WGS. Sanger verification.
Testing laboratory: Clinical Genomics - SciLifeLab Solna (Sweden)
Date variant was reported to submitter: 2018-03-29
|
|
| Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more | |||||
Comment:
Comment:
This sequence change disrupts the translational stop signal of the PAX6 mRNA. It is expected to extend the length of the PAX6 protein by 14 additional amino acid residues. This variant is not present in population databases (gnomAD no frequency). This protein extension has been observed in individual(s) with aniridia (PMID: 11309364, 12552561, 27431685, 28321846, 29618921). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is also known as c.1290 A>T and X437L. ClinVar contains an entry for this variant (Variation ID: 3474). For these reasons, this variant has been classified as Pathogenic.
Comment:
PAX6: PP1:Strong, PM2, PM4, PS4:Moderate, PM6:Supporting, PP4
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:
Normal stop codon changed to a Leucine codon, leading to the addition of 14 amino acids at the C-terminus; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18494745, 20132240, 28321846, 21850189, 25555363, 22204637, 16098226, 6330922, 18494744, 16199712, 22361317, 28698011, 18241071, 10477494, 11309364, 26661695, 12552561, 27431685, 29618921, 29367200, 32360764, 33594928, 27535533, 34101622, 33726816, 32467297)
Comment:
This sequence change disrupts the translational stop signal of the PAX6 mRNA. It is expected to extend the length of the PAX6 protein by 14 additional amino acid residues. This variant is not present in population databases (gnomAD no frequency). This protein extension has been observed in individual(s) with aniridia (PMID: 11309364, 12552561, 27431685, 28321846, 29618921). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is also known as c.1290 A>T and X437L. ClinVar contains an entry for this variant (Variation ID: 3474). For these reasons, this variant has been classified as Pathogenic.
Comment:
PAX6: PP1:Strong, PM2, PM4, PS4:Moderate, PM6:Supporting, PP4
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| PAX6 molecular analysis and genotype-phenotype correlations in families with aniridia from Australasia and Southeast Asia. | Souzeau E | Molecular vision | 2018 | PMID: 29618921 |
| Molecular analysis of patients with aniridia in Russian Federation broadens the spectrum of PAX6 mutations. | Vasilyeva TA | Clinical genetics | 2017 | PMID: 28321846 |
| Identification of a novel frameshift heterozygous deletion in exon 8 of the PAX6 gene in a pedigree with aniridia. | Giray Bozkaya O | Molecular medicine reports | 2016 | PMID: 27431685 |
| A screen for proteins that interact with PAX6: C-terminal mutations disrupt interaction with HOMER3, DNCL1 and TRIM11. | Cooper ST | BMC genetics | 2005 | PMID: 16098226 |
| Polymicrogyria and absence of pineal gland due to PAX6 mutation. | Mitchell TN | Annals of neurology | 2003 | PMID: 12731001 |
| Missense mutations in the DNA-binding region and termination codon in PAX6. | Chao LY | Human mutation | 2003 | PMID: 12552561 |
| PAX6 haploinsufficiency causes cerebral malformation and olfactory dysfunction in humans. | Sisodiya SM | Nature genetics | 2001 | PMID: 11431688 |
| Missense mutation at the C-terminus of PAX6 negatively modulates homeodomain function. | Singh S | Human molecular genetics | 2001 | PMID: 11309364 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PAX6 | - | - | - | - |
Text-mined citations for rs121907922 ...
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 Oct 20, 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.