Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate that R317X results in reduced activation of reporter genes compared to wild type (Chauhan et al., 2004); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 26661695, 12868034, 21850189, 19898691, 25525159, 14744876, 27381094, 8111379, 27081561, 29901133, 12634864, 32360764, 34101622, 21397818, 15020706)
ClinVar Genomic variation as it relates to human health
NM_001368894.2(PAX6):c.991C>T (p.Arg331Ter)
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.
(4)
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
4
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.991C>T (p.Arg331Ter)
Variation ID: 372444 Accession: VCV000372444.37
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p13 11: 31793521 (GRCh38) [ NCBI UCSC ] 11: 31815069 (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 Jan 9, 2017 Oct 20, 2024 Jul 1, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001368894.2:c.991C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001355823.1:p.Arg331Ter nonsense NM_000280.6:c.949C>T NP_000271.1:p.Arg317Ter nonsense NM_001127612.3:c.949C>T NP_001121084.1:p.Arg317Ter nonsense NM_001258462.3:c.991C>T NP_001245391.1:p.Arg331Ter nonsense NM_001258463.2:c.991C>T NP_001245392.1:p.Arg331Ter nonsense NM_001258464.2:c.949C>T NP_001245393.1:p.Arg317Ter nonsense NM_001258465.3:c.949C>T NP_001245394.1:p.Arg317Ter nonsense NM_001310158.2:c.991C>T NP_001297087.1:p.Arg331Ter nonsense NM_001310159.1:c.949C>T NP_001297088.1:p.Arg317Ter nonsense NM_001310160.2:c.541C>T NP_001297089.1:p.Arg181Ter nonsense NM_001310161.3:c.541C>T NP_001297090.1:p.Arg181Ter nonsense NM_001368887.2:c.949C>T NP_001355816.1:p.Arg317Ter nonsense NM_001368888.2:c.949C>T NP_001355817.1:p.Arg317Ter nonsense NM_001368889.2:c.949C>T NP_001355818.1:p.Arg317Ter nonsense NM_001368890.2:c.949C>T NP_001355819.1:p.Arg317Ter nonsense NM_001368891.2:c.949C>T NP_001355820.1:p.Arg317Ter nonsense NM_001368892.2:c.991C>T NP_001355821.1:p.Arg331Ter nonsense NM_001368893.2:c.991C>T NP_001355822.1:p.Arg331Ter nonsense NM_001368899.2:c.541C>T NP_001355828.1:p.Arg181Ter nonsense NM_001368900.2:c.541C>T NP_001355829.1:p.Arg181Ter nonsense NM_001368901.2:c.541C>T NP_001355830.1:p.Arg181Ter nonsense NM_001368902.2:c.541C>T NP_001355831.1:p.Arg181Ter nonsense NM_001368903.2:c.541C>T NP_001355832.1:p.Arg181Ter nonsense NM_001368904.2:c.541C>T NP_001355833.1:p.Arg181Ter nonsense NM_001368905.2:c.541C>T NP_001355834.1:p.Arg181Ter nonsense NM_001368906.2:c.541C>T NP_001355835.1:p.Arg181Ter nonsense NM_001368907.2:c.541C>T NP_001355836.1:p.Arg181Ter nonsense NM_001368908.2:c.541C>T NP_001355837.1:p.Arg181Ter nonsense NM_001368909.2:c.541C>T NP_001355838.1:p.Arg181Ter nonsense NM_001368910.2:c.1192C>T NP_001355839.1:p.Arg398Ter nonsense NM_001368911.2:c.994C>T NP_001355840.1:p.Arg332Ter nonsense NM_001368912.2:c.991C>T NP_001355841.1:p.Arg331Ter nonsense NM_001368913.2:c.991C>T NP_001355842.1:p.Arg331Ter nonsense NM_001368914.2:c.991C>T NP_001355843.1:p.Arg331Ter nonsense NM_001368915.2:c.949C>T NP_001355844.1:p.Arg317Ter nonsense NM_001368916.2:c.949C>T NP_001355845.1:p.Arg317Ter nonsense NM_001368917.2:c.949C>T NP_001355846.1:p.Arg317Ter nonsense NM_001368918.2:c.1066C>T NP_001355847.1:p.Arg356Ter nonsense NM_001368919.2:c.1066C>T NP_001355848.1:p.Arg356Ter nonsense NM_001368920.2:c.1024C>T NP_001355849.1:p.Arg342Ter nonsense NM_001368921.2:c.790C>T NP_001355850.1:p.Arg264Ter nonsense NM_001368922.2:c.790C>T NP_001355851.1:p.Arg264Ter nonsense NM_001368923.2:c.790C>T NP_001355852.1:p.Arg264Ter nonsense NM_001368924.2:c.790C>T NP_001355853.1:p.Arg264Ter nonsense NM_001368925.2:c.790C>T NP_001355854.1:p.Arg264Ter nonsense NM_001368926.2:c.790C>T NP_001355855.1:p.Arg264Ter nonsense NM_001368927.2:c.790C>T NP_001355856.1:p.Arg264Ter nonsense NM_001368928.2:c.748C>T NP_001355857.1:p.Arg250Ter nonsense NM_001368929.2:c.541C>T NP_001355858.1:p.Arg181Ter nonsense NM_001368930.2:c.346C>T NP_001355859.1:p.Arg116Ter nonsense NM_001604.6:c.991C>T NP_001595.2:p.Arg331Ter nonsense NR_160916.2:n.1330C>T non-coding transcript variant NR_160917.2:n.1335C>T non-coding transcript variant NC_000011.10:g.31793521G>A NC_000011.9:g.31815069G>A NG_008679.1:g.29441C>T LRG_720:g.29441C>T LRG_720t1:c.949C>T - Protein change
- R317*, R116*, R342*, R181*, R356*, R250*, R264*, R331*, R332*, R398*
- Other names
- -
- Canonical SPDI
- NC_000011.10:31793520:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
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Allele frequency
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 | |
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
|
Jul 1, 2024 | RCV000413962.26 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 8, 2023 | RCV000557326.8 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Aug 15, 2019 | RCV000984450.2 |
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
(Aug 15, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Aniridia 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown,
de novo,
inherited
|
Wessex Regional Genetics Laboratory, Salisbury District Hospital
Accession: SCV001055809.1
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
|
|
|
Pathogenic
(Nov 18, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000490696.4
First in ClinVar: Jan 09, 2017 Last updated: Mar 04, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate that R317X results in reduced activation of reporter genes compared to wild type (Chauhan et al., 2004); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 26661695, 12868034, 21850189, 19898691, 25525159, 14744876, 27381094, 8111379, 27081561, 29901133, 12634864, 32360764, 34101622, 21397818, 15020706) (less)
|
|
|
Pathogenic
(Mar 08, 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: SCV000632671.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 372444). This premature translational stop signal … (more)
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 372444). This premature translational stop signal has been observed in individuals with aniridia (PMID: 8111279, 19898691, 21397818, 22692063, 26661695). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg317*) in the PAX6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PAX6 are known to be pathogenic (PMID: 12634864). (less)
|
|
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Pathogenic
(Jul 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001247621.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Comment:
PAX6: PVS1, PP1:Strong, PS2, PM2, PS4:Moderate, PS3:Supporting
Number of individuals with the variant: 2
|
Comment:
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 372444). This premature translational stop signal has been observed in individuals with aniridia (PMID: 8111279, 19898691, 21397818, 22692063, 26661695). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg317*) in the PAX6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PAX6 are known to be pathogenic (PMID: 12634864).
Comment:
PAX6: PVS1, PP1:Strong, PS2, PM2, PS4:Moderate, PS3:Supporting
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:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate that R317X results in reduced activation of reporter genes compared to wild type (Chauhan et al., 2004); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 26661695, 12868034, 21850189, 19898691, 25525159, 14744876, 27381094, 8111379, 27081561, 29901133, 12634864, 32360764, 34101622, 21397818, 15020706)
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 372444). This premature translational stop signal has been observed in individuals with aniridia (PMID: 8111279, 19898691, 21397818, 22692063, 26661695). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg317*) in the PAX6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PAX6 are known to be pathogenic (PMID: 12634864).
Comment:
PAX6: PVS1, PP1:Strong, PS2, PM2, PS4:Moderate, PS3:Supporting
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Assessment of PAX6 alleles in 66 families with aniridia. | Bobilev AM | Clinical genetics | 2016 | PMID: 26661695 |
| Aniridia. | Hingorani M | European journal of human genetics : EJHG | 2012 | PMID: 22692063 |
| A case of aniridia with unilateral Peters anomaly. | Sawada M | Journal of AAPOS : the official publication of the American Association for Pediatric Ophthalmology and Strabismus | 2011 | PMID: 21397818 |
| Eye anomalies and neurological manifestations in patients with PAX6 mutations. | Chien YH | Molecular vision | 2009 | PMID: 19898691 |
| Screening for PAX6 gene mutations is consistent with haploinsufficiency as the main mechanism leading to various ocular defects. | Vincent MC | European journal of human genetics : EJHG | 2003 | PMID: 12634864 |
| Safe blood? HTLV-1 infection is crippling. | Copplestone JA | BMJ (Clinical research ed.) | 1994 | PMID: 8111279 |
Text-mined citations for rs1057517785 ...
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.