This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 78 of the PAX6 protein (p.Val78Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PAX6-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PAX6 protein function with a positive predictive value of 80%. This variant disrupts the p.Val78 amino acid residue in PAX6. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 30167917, 34415986). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
ClinVar Genomic variation as it relates to human health
NM_001368894.2(PAX6):c.274G>C (p.Val92Leu)
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.
(1)
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.
Uncertain significance
1
criteria provided, single submitter
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001368894.2(PAX6):c.274G>C (p.Val92Leu)
Variation ID: 2942049 Accession: VCV002942049.1
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p13 11: 31801686 (GRCh38) [ NCBI UCSC ] 11: 31823234 (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 Feb 29, 2024 Feb 28, 2024 Jan 10, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001368894.2:c.274G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001355823.1:p.Val92Leu missense NM_000280.6:c.232G>C NP_000271.1:p.Val78Leu missense NM_001127612.3:c.232G>C NP_001121084.1:p.Val78Leu missense NM_001258462.3:c.274G>C NP_001245391.1:p.Val92Leu missense NM_001258463.2:c.274G>C NP_001245392.1:p.Val92Leu missense NM_001258464.2:c.232G>C NP_001245393.1:p.Val78Leu missense NM_001258465.3:c.232G>C NP_001245394.1:p.Val78Leu missense NM_001310158.2:c.274G>C NP_001297087.1:p.Val92Leu missense NM_001310159.1:c.232G>C NP_001297088.1:p.Val78Leu missense NM_001310160.2:c.-508G>C 5 prime UTR NM_001310161.3:c.-177G>C 5 prime UTR NM_001368887.2:c.232G>C NP_001355816.1:p.Val78Leu missense NM_001368888.2:c.232G>C NP_001355817.1:p.Val78Leu missense NM_001368889.2:c.232G>C NP_001355818.1:p.Val78Leu missense NM_001368890.2:c.232G>C NP_001355819.1:p.Val78Leu missense NM_001368891.2:c.232G>C NP_001355820.1:p.Val78Leu missense NM_001368892.2:c.274G>C NP_001355821.1:p.Val92Leu missense NM_001368893.2:c.274G>C NP_001355822.1:p.Val92Leu missense NM_001368899.2:c.-177G>C 5 prime UTR NM_001368900.2:c.-177G>C 5 prime UTR NM_001368901.2:c.-177G>C 5 prime UTR NM_001368902.2:c.-508G>C 5 prime UTR NM_001368903.2:c.-177G>C 5 prime UTR NM_001368904.2:c.-177G>C 5 prime UTR NM_001368905.2:c.-508G>C 5 prime UTR NM_001368906.2:c.-177G>C 5 prime UTR NM_001368907.2:c.-177G>C 5 prime UTR NM_001368908.2:c.-177G>C 5 prime UTR NM_001368909.2:c.-177G>C 5 prime UTR NM_001368910.2:c.475G>C NP_001355839.1:p.Val159Leu missense NM_001368911.2:c.277G>C NP_001355840.1:p.Val93Leu missense NM_001368912.2:c.274G>C NP_001355841.1:p.Val92Leu missense NM_001368913.2:c.274G>C NP_001355842.1:p.Val92Leu missense NM_001368914.2:c.274G>C NP_001355843.1:p.Val92Leu missense NM_001368915.2:c.232G>C NP_001355844.1:p.Val78Leu missense NM_001368916.2:c.232G>C NP_001355845.1:p.Val78Leu missense NM_001368917.2:c.232G>C NP_001355846.1:p.Val78Leu missense NM_001368918.2:c.349G>C NP_001355847.1:p.Val117Leu missense NM_001368919.2:c.349G>C NP_001355848.1:p.Val117Leu missense NM_001368920.2:c.307G>C NP_001355849.1:p.Val103Leu missense NM_001368921.2:c.198+76G>C intron variant NM_001368922.2:c.198+76G>C intron variant NM_001368923.2:c.198+76G>C intron variant NM_001368924.2:c.198+76G>C intron variant NM_001368925.2:c.198+76G>C intron variant NM_001368926.2:c.198+76G>C intron variant NM_001368927.2:c.198+76G>C intron variant NM_001368928.2:c.156+76G>C intron variant NM_001368929.2:c.-177G>C 5 prime UTR NM_001604.6:c.274G>C NP_001595.2:p.Val92Leu missense NR_160916.2:n.696G>C non-coding transcript variant NR_160917.2:n.701G>C non-coding transcript variant NC_000011.10:g.31801686C>G NC_000011.9:g.31823234C>G NG_008679.1:g.21276G>C LRG_720:g.21276G>C LRG_720t1:c.232G>C LRG_720p1:p.Val78Leu - Protein change
- V117L, V78L, V93L, V103L, V159L, V92L
- Other names
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- Canonical SPDI
- NC_000011.10:31801685:C:G
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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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- 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. |
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| PAX6 | Sufficient evidence for dosage pathogenicity | Little evidence for dosage pathogenicity |
GRCh38 GRCh37 |
698 | 902 | |
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. |
|---|---|---|---|---|
| Uncertain significance (1) |
criteria provided, single submitter
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Jan 10, 2024 | RCV003803071.2 |
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. |
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Uncertain significance
(Jan 10, 2024)
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criteria provided, single submitter
Method: clinical testing
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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
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004592970.1
First in ClinVar: Feb 28, 2024 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 78 of the PAX6 protein (p.Val78Leu). … (more)
This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 78 of the PAX6 protein (p.Val78Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PAX6-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PAX6 protein function with a positive predictive value of 80%. This variant disrupts the p.Val78 amino acid residue in PAX6. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 30167917, 34415986). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
|
Comment:
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:
This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 78 of the PAX6 protein (p.Val78Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PAX6-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PAX6 protein function with a positive predictive value of 80%. This variant disrupts the p.Val78 amino acid residue in PAX6. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 30167917, 34415986). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Genotype-Phenotype of Isolated Foveal Hypoplasia in a Large Cohort: Minor Iris Changes as an Indicator of PAX6 Involvement. | Jiang Y | Investigative ophthalmology & visual science | 2021 | PMID: 34415986 |
| Mild aniridia phenotype: an under-recognized diagnosis of a severe inherited ocular disease. | Yahalom C | Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie | 2018 | PMID: 30167917 |
Text-mined citations for this variant ...
HelpRecord last updated Sep 30, 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.