VCV000279862.46 - ClinVar

NM_001368894.2(PAX6):c.823C>T (p.Arg275Ter)

Germline

Classification

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)

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

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.823C>T (p.Arg275Ter)

Variation ID: 279862 Accession: VCV000279862.46

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p13 11: 31793787 (GRCh38) [ NCBI UCSC ] 11: 31815335 (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	Dec 6, 2016	Jul 23, 2024	Jul 16, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001368894.2:c.823C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001355823.1:p.Arg275Ter	nonsense
NM_000280.6:c.781C>T	NP_000271.1:p.Arg261Ter	nonsense
NM_001127612.3:c.781C>T	NP_001121084.1:p.Arg261Ter	nonsense
NM_001258462.3:c.823C>T	NP_001245391.1:p.Arg275Ter	nonsense
NM_001258463.2:c.823C>T	NP_001245392.1:p.Arg275Ter	nonsense
NM_001258464.2:c.781C>T	NP_001245393.1:p.Arg261Ter	nonsense
NM_001258465.3:c.781C>T	NP_001245394.1:p.Arg261Ter	nonsense
NM_001310158.2:c.823C>T	NP_001297087.1:p.Arg275Ter	nonsense
NM_001310159.1:c.781C>T	NP_001297088.1:p.Arg261Ter	nonsense
NM_001310160.1:c.373C>T
NM_001310160.2:c.373C>T	NP_001297089.1:p.Arg125Ter	nonsense
NM_001310161.3:c.373C>T	NP_001297090.1:p.Arg125Ter	nonsense
NM_001368887.2:c.781C>T	NP_001355816.1:p.Arg261Ter	nonsense
NM_001368888.2:c.781C>T	NP_001355817.1:p.Arg261Ter	nonsense
NM_001368889.2:c.781C>T	NP_001355818.1:p.Arg261Ter	nonsense
NM_001368890.2:c.781C>T	NP_001355819.1:p.Arg261Ter	nonsense
NM_001368891.2:c.781C>T	NP_001355820.1:p.Arg261Ter	nonsense
NM_001368892.2:c.823C>T	NP_001355821.1:p.Arg275Ter	nonsense
NM_001368893.2:c.823C>T	NP_001355822.1:p.Arg275Ter	nonsense
NM_001368899.2:c.373C>T	NP_001355828.1:p.Arg125Ter	nonsense
NM_001368900.2:c.373C>T	NP_001355829.1:p.Arg125Ter	nonsense
NM_001368901.2:c.373C>T	NP_001355830.1:p.Arg125Ter	nonsense
NM_001368902.2:c.373C>T	NP_001355831.1:p.Arg125Ter	nonsense
NM_001368903.2:c.373C>T	NP_001355832.1:p.Arg125Ter	nonsense
NM_001368904.2:c.373C>T	NP_001355833.1:p.Arg125Ter	nonsense
NM_001368905.2:c.373C>T	NP_001355834.1:p.Arg125Ter	nonsense
NM_001368906.2:c.373C>T	NP_001355835.1:p.Arg125Ter	nonsense
NM_001368907.2:c.373C>T	NP_001355836.1:p.Arg125Ter	nonsense
NM_001368908.2:c.373C>T	NP_001355837.1:p.Arg125Ter	nonsense
NM_001368909.2:c.373C>T	NP_001355838.1:p.Arg125Ter	nonsense
NM_001368910.2:c.1024C>T	NP_001355839.1:p.Arg342Ter	nonsense
NM_001368911.2:c.826C>T	NP_001355840.1:p.Arg276Ter	nonsense
NM_001368912.2:c.823C>T	NP_001355841.1:p.Arg275Ter	nonsense
NM_001368913.2:c.823C>T	NP_001355842.1:p.Arg275Ter	nonsense
NM_001368914.2:c.823C>T	NP_001355843.1:p.Arg275Ter	nonsense
NM_001368915.2:c.781C>T	NP_001355844.1:p.Arg261Ter	nonsense
NM_001368916.2:c.781C>T	NP_001355845.1:p.Arg261Ter	nonsense
NM_001368917.2:c.781C>T	NP_001355846.1:p.Arg261Ter	nonsense
NM_001368918.2:c.898C>T	NP_001355847.1:p.Arg300Ter	nonsense
NM_001368919.2:c.898C>T	NP_001355848.1:p.Arg300Ter	nonsense
NM_001368920.2:c.856C>T	NP_001355849.1:p.Arg286Ter	nonsense
NM_001368921.2:c.622C>T	NP_001355850.1:p.Arg208Ter	nonsense
NM_001368922.2:c.622C>T	NP_001355851.1:p.Arg208Ter	nonsense
NM_001368923.2:c.622C>T	NP_001355852.1:p.Arg208Ter	nonsense
NM_001368924.2:c.622C>T	NP_001355853.1:p.Arg208Ter	nonsense
NM_001368925.2:c.622C>T	NP_001355854.1:p.Arg208Ter	nonsense
NM_001368926.2:c.622C>T	NP_001355855.1:p.Arg208Ter	nonsense
NM_001368927.2:c.622C>T	NP_001355856.1:p.Arg208Ter	nonsense
NM_001368928.2:c.580C>T	NP_001355857.1:p.Arg194Ter	nonsense
NM_001368929.2:c.373C>T	NP_001355858.1:p.Arg125Ter	nonsense
NM_001368930.2:c.178C>T	NP_001355859.1:p.Arg60Ter	nonsense
NM_001604.6:c.823C>T	NP_001595.2:p.Arg275Ter	nonsense
NR_160916.2:n.1162C>T		non-coding transcript variant
NR_160917.2:n.1167C>T		non-coding transcript variant
NC_000011.10:g.31793787G>A
NC_000011.9:g.31815335G>A
NG_008679.1:g.29175C>T
LRG_720:g.29175C>T
LRG_720t1:c.781C>T

... more HGVS ... less HGVS

Protein change

R261*, R125*, R208*, R276*, R300*, R342*, R60*, R194*, R275*, R286*

Other names

Canonical SPDI

NC_000011.10:31793786:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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

ClinGen: CA10603114 dbSNP: rs886041222 VarSome

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
Gene	OMIM	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.
not provided	Pathogenic (1)	criteria provided, single submitter	Mar 18, 2021	RCV000272207.10
Aniridia 1	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Jul 16, 2023	RCV000496007.14
Aniridia 1 Irido-corneo-trabecular dysgenesis	Pathogenic (1)	criteria provided, single submitter	Apr 7, 2023	RCV000547174.16
11p partial monosomy syndrome Aniridia 1 Autosomal dominant keratitis Coloboma of optic nerve Congenital ocular coloboma Foveal hypoplasia 1 Irido-corneo-trabecular dysgenesis Isolated optic nerve hypoplasia	Pathogenic (1)	criteria provided, single submitter	Oct 31, 2018	RCV000762839.9
PAX6-related disorder	Pathogenic (1)	criteria provided, single submitter	Apr 27, 2023	RCV004545764.1

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.
Pathogenic (Jul 31, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Aniridia 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: unknown	Genetics and Molecular Pathology, SA Pathology Study: ANZRAG Accession: SCV000692535.1 First in ClinVar: Jul 30, 2017 Last updated: Jul 30, 2017	Number of individuals with the variant: 1 Family history: yes Sex: female Ethnicity/Population group: Caucasian Geographic origin: Australia Secondary finding: no
Pathogenic (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) 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: SCV000893198.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (Aug 15, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) 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: SCV001055793.1 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 (Mar 18, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000329452.7 First in ClinVar: Dec 06, 2016 Last updated: Jul 24, 2021	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; Not … (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; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 33120723, 31861090, 22692063, 18483559, 28321846, 29618921, 12634864, 26661695, 10234503, 25525159, 32360764) (less)
Pathogenic (Apr 07, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) 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: SCV000632670.7 First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024	Publications: PubMed (6) PubMed: 10234503‚ 18483559‚ 22692063‚ 26661695‚ 28321846‚ 12634864 Comment: For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 279862). 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: 279862). This premature translational stop signal has been observed in individual(s) with aniridia (PMID: 10234503, 18483559, 22692063, 26661695, 28321846). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg261*) 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)
Pathogenic (Apr 27, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	PAX6-related disorders Affected status: yes Allele origin: germline	Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL) Accession: SCV003920785.1 First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023
Pathogenic (Jul 16, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Aniridia 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002769300.2 First in ClinVar: Dec 24, 2022 Last updated: Jul 23, 2024	Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with PAX6-related conditions. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar. (SP) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (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: SCV000584157.1 First in ClinVar: Jul 30, 2017 Last updated: Jul 30, 2017	Publications: PubMed (1) PubMed: 28321846 Geographic origin: Russia Method: Sanger sequencing

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; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 33120723, 31861090, 22692063, 18483559, 28321846, 29618921, 12634864, 26661695, 10234503, 25525159, 32360764)

Comment:

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 279862). This premature translational stop signal has been observed in individual(s) with aniridia (PMID: 10234503, 18483559, 22692063, 26661695, 28321846). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg261*) 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:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with PAX6-related conditions. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar. (SP) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Molecular analysis of patients with aniridia in Russian Federation broadens the spectrum of PAX6 mutations.	Vasilyeva TA	Clinical genetics	2017	PMID: 28321846
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
Multiplex ligation-dependent probe amplification (MLPA) enhances the molecular diagnosis of aniridia and related disorders.	Redeker EJ	Molecular vision	2008	PMID: 18483559
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
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

Text-mined citations for rs886041222 ...

These 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

ClinVar Genomic variation as it relates to human health

NM_001368894.2(PAX6):c.823C>T (p.Arg275Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs886041222 ...