In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9147640, 12015275, 7550230, 8364574, 9482572, 10234503, 22361317, 10737978, 29450879, 32360764, 34415986, 29930474, 34344282, 35170016)
ClinVar Genomic variation as it relates to human health
NM_001368894.2(PAX6):c.664C>T (p.Arg222Trp)
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.
(7)
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
7
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.664C>T (p.Arg222Trp)
Variation ID: 372441 Accession: VCV000372441.20
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p13 11: 31794690 (GRCh38) [ NCBI UCSC ] 11: 31816238 (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 Jan 9, 2017 Feb 28, 2024 Jun 1, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001368894.2:c.664C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001355823.1:p.Arg222Trp missense NM_000280.6:c.622C>T NP_000271.1:p.Arg208Trp missense NM_001127612.3:c.622C>T NP_001121084.1:p.Arg208Trp missense NM_001258462.3:c.664C>T NP_001245391.1:p.Arg222Trp missense NM_001258463.2:c.664C>T NP_001245392.1:p.Arg222Trp missense NM_001258464.2:c.622C>T NP_001245393.1:p.Arg208Trp missense NM_001258465.3:c.622C>T NP_001245394.1:p.Arg208Trp missense NM_001310158.2:c.664C>T NP_001297087.1:p.Arg222Trp missense NM_001310159.1:c.622C>T NP_001297088.1:p.Arg208Trp missense NM_001310160.2:c.214C>T NP_001297089.1:p.Arg72Trp missense NM_001310161.3:c.214C>T NP_001297090.1:p.Arg72Trp missense NM_001368887.2:c.622C>T NP_001355816.1:p.Arg208Trp missense NM_001368888.2:c.622C>T NP_001355817.1:p.Arg208Trp missense NM_001368889.2:c.622C>T NP_001355818.1:p.Arg208Trp missense NM_001368890.2:c.622C>T NP_001355819.1:p.Arg208Trp missense NM_001368891.2:c.622C>T NP_001355820.1:p.Arg208Trp missense NM_001368892.2:c.664C>T NP_001355821.1:p.Arg222Trp missense NM_001368893.2:c.664C>T NP_001355822.1:p.Arg222Trp missense NM_001368899.2:c.214C>T NP_001355828.1:p.Arg72Trp missense NM_001368900.2:c.214C>T NP_001355829.1:p.Arg72Trp missense NM_001368901.2:c.214C>T NP_001355830.1:p.Arg72Trp missense NM_001368902.2:c.214C>T NP_001355831.1:p.Arg72Trp missense NM_001368903.2:c.214C>T NP_001355832.1:p.Arg72Trp missense NM_001368904.2:c.214C>T NP_001355833.1:p.Arg72Trp missense NM_001368905.2:c.214C>T NP_001355834.1:p.Arg72Trp missense NM_001368906.2:c.214C>T NP_001355835.1:p.Arg72Trp missense NM_001368907.2:c.214C>T NP_001355836.1:p.Arg72Trp missense NM_001368908.2:c.214C>T NP_001355837.1:p.Arg72Trp missense NM_001368909.2:c.214C>T NP_001355838.1:p.Arg72Trp missense NM_001368910.2:c.865C>T NP_001355839.1:p.Arg289Trp missense NM_001368911.2:c.667C>T NP_001355840.1:p.Arg223Trp missense NM_001368912.2:c.664C>T NP_001355841.1:p.Arg222Trp missense NM_001368913.2:c.664C>T NP_001355842.1:p.Arg222Trp missense NM_001368914.2:c.664C>T NP_001355843.1:p.Arg222Trp missense NM_001368915.2:c.622C>T NP_001355844.1:p.Arg208Trp missense NM_001368916.2:c.622C>T NP_001355845.1:p.Arg208Trp missense NM_001368917.2:c.622C>T NP_001355846.1:p.Arg208Trp missense NM_001368918.2:c.739C>T NP_001355847.1:p.Arg247Trp missense NM_001368919.2:c.739C>T NP_001355848.1:p.Arg247Trp missense NM_001368920.2:c.697C>T NP_001355849.1:p.Arg233Trp missense NM_001368921.2:c.463C>T NP_001355850.1:p.Arg155Trp missense NM_001368922.2:c.463C>T NP_001355851.1:p.Arg155Trp missense NM_001368923.2:c.463C>T NP_001355852.1:p.Arg155Trp missense NM_001368924.2:c.463C>T NP_001355853.1:p.Arg155Trp missense NM_001368925.2:c.463C>T NP_001355854.1:p.Arg155Trp missense NM_001368926.2:c.463C>T NP_001355855.1:p.Arg155Trp missense NM_001368927.2:c.463C>T NP_001355856.1:p.Arg155Trp missense NM_001368928.2:c.421C>T NP_001355857.1:p.Arg141Trp missense NM_001368929.2:c.214C>T NP_001355858.1:p.Arg72Trp missense NM_001368930.2:c.19C>T NP_001355859.1:p.Arg7Trp missense NM_001604.5:c.664C>T NM_001604.6:c.664C>T NP_001595.2:p.Arg222Trp missense NR_160916.2:n.1086C>T non-coding transcript variant NR_160917.2:n.1091C>T non-coding transcript variant NC_000011.10:g.31794690G>A NC_000011.9:g.31816238G>A NG_008679.1:g.28272C>T LRG_720:g.28272C>T LRG_720t1:c.622C>T - Protein change
- R208W, R247W, R223W, R141W, R222W, R72W, R7W, R155W, R233W, R289W
- Other names
- -
- Canonical SPDI
- NC_000011.10:31794689: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.
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The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
- 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/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Aug 8, 2022 | RCV000413794.8 | |
| Pathogenic (2) |
criteria provided, single submitter
|
Jul 21, 2020 | RCV000984424.7 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Feb 17, 2022 | RCV001388984.7 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 1, 2022 | RCV002463362.2 | |
|
PAX6-related disorder
|
Pathogenic (1) |
criteria provided, single submitter
|
Jun 1, 2023 | RCV004529567.1 |
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. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(May 08, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000708115.2
First in ClinVar: Apr 02, 2018 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
|
|
|
Pathogenic
(Aug 08, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000490693.4
First in ClinVar: Jan 09, 2017 Last updated: Mar 04, 2023 |
Comment:
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (gnomAD); … (more)
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9147640, 12015275, 7550230, 8364574, 9482572, 10234503, 22361317, 10737978, 29450879, 32360764, 34415986, 29930474, 34344282, 35170016) (less)
|
|
|
Pathogenic
(Jul 21, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Aniridia 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV001430017.1
First in ClinVar: Aug 21, 2020 Last updated: Aug 21, 2020 |
Clinical Features:
Nystagmus (present) , Frontotemporal dementia (present) , Atypical behavior (present) , Short stepped shuffling gait (present) , Visual impairment (present) , Tremor (present)
Sex: female
Tissue: blood
|
|
|
Pathogenic
(Dec 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Foveal hypoplasia 1
Irido-corneo-trabecular dysgenesis (Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV002757803.1
First in ClinVar: Dec 03, 2022 Last updated: Dec 03, 2022 |
Clinical Features:
Visual impairment (present) , Esotropia (present) , Photophobia (present) , Congenital nystagmus (present)
|
|
|
Pathogenic
(Jun 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
PAX6-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004107619.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The PAX6 c.664C>T variant is predicted to result in the amino acid substitution p.Arg222Trp. This variant can also be designated c.622C>T (p.Arg208Trp) in transcript NM_001258464.1. … (more)
The PAX6 c.664C>T variant is predicted to result in the amino acid substitution p.Arg222Trp. This variant can also be designated c.622C>T (p.Arg208Trp) in transcript NM_001258464.1. This variant has been reported multiple times in individuals with PAX6-related disease, and in some cases was confirmed de novo (reported as c.622C>T p.Arg208Trp in Patel et al. 2018. PubMed ID: 29450879; Cross et al. 2020. PubMed ID: 32360764; Chesneau et al. 2022. PubMed ID: 35170016). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-31816238-G-A). This variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/372441/). Given all the evidence, we interpret c.664C>T (p.Arg222Trp) as pathogenic. (less)
|
|
|
Pathogenic
(Feb 17, 2022)
|
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: SCV001590181.4
First in ClinVar: May 10, 2021 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg208 amino acid residue in PAX6. Other variant(s) that disrupt this … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg208 amino acid residue in PAX6. Other variant(s) that disrupt this residue have been observed in individuals with PAX6-related conditions (PMID: 10234503), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 372441). This missense change has been observed in individuals with aniridia or congenital cataracts (PMID: 8364574, 22361317). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs757259413, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 208 of the PAX6 protein (p.Arg208Trp). (less)
|
|
|
Likely pathogenic
(Aug 15, 2019)
|
no assertion criteria provided
Method: clinical testing
|
Aniridia 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
inherited
|
Wessex Regional Genetics Laboratory, Salisbury District Hospital
Accession: SCV001055779.1
First in ClinVar: Dec 23, 2019 Last updated: Dec 23, 2019 |
|
Comment:
Comment:
The PAX6 c.664C>T variant is predicted to result in the amino acid substitution p.Arg222Trp. This variant can also be designated c.622C>T (p.Arg208Trp) in transcript NM_001258464.1. This variant has been reported multiple times in individuals with PAX6-related disease, and in some cases was confirmed de novo (reported as c.622C>T p.Arg208Trp in Patel et al. 2018. PubMed ID: 29450879; Cross et al. 2020. PubMed ID: 32360764; Chesneau et al. 2022. PubMed ID: 35170016). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-31816238-G-A). This variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/372441/). Given all the evidence, we interpret c.664C>T (p.Arg222Trp) as pathogenic.
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg208 amino acid residue in PAX6. Other variant(s) that disrupt this residue have been observed in individuals with PAX6-related conditions (PMID: 10234503), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 372441). This missense change has been observed in individuals with aniridia or congenital cataracts (PMID: 8364574, 22361317). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs757259413, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 208 of the PAX6 protein (p.Arg208Trp).
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:
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9147640, 12015275, 7550230, 8364574, 9482572, 10234503, 22361317, 10737978, 29450879, 32360764, 34415986, 29930474, 34344282, 35170016)
Comment:
The PAX6 c.664C>T variant is predicted to result in the amino acid substitution p.Arg222Trp. This variant can also be designated c.622C>T (p.Arg208Trp) in transcript NM_001258464.1. This variant has been reported multiple times in individuals with PAX6-related disease, and in some cases was confirmed de novo (reported as c.622C>T p.Arg208Trp in Patel et al. 2018. PubMed ID: 29450879; Cross et al. 2020. PubMed ID: 32360764; Chesneau et al. 2022. PubMed ID: 35170016). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-31816238-G-A). This variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/372441/). Given all the evidence, we interpret c.664C>T (p.Arg222Trp) as pathogenic.
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg208 amino acid residue in PAX6. Other variant(s) that disrupt this residue have been observed in individuals with PAX6-related conditions (PMID: 10234503), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 372441). This missense change has been observed in individuals with aniridia or congenital cataracts (PMID: 8364574, 22361317). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs757259413, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 208 of the PAX6 protein (p.Arg208Trp).
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Comparison between aniridia with and without PAX6 mutations: clinical and molecular analysis in 14 Korean patients with aniridia. | Lim HT | Ophthalmology | 2012 | PMID: 22361317 |
| Mutational analysis of PAX6: 16 novel mutations including 5 missense mutations with a mild aniridia phenotype. | Grønskov K | European journal of human genetics : EJHG | 1999 | PMID: 10234503 |
| PAX6 mutations in aniridia. | Hanson IM | Human molecular genetics | 1993 | PMID: 8364574 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PAX6 | - | - | - | - |
Text-mined citations for rs757259413 ...
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 Nov 25, 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.