VCV000390567.5 - ClinVar

NM_001368894.2(PAX6):c.959-3C>G

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.

(2)

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

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.959-3C>G

Variation ID: 390567 Accession: VCV000390567.5

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p13 11: 31793556 (GRCh38) [ NCBI UCSC ] 11: 31815104 (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	Mar 8, 2017	Feb 28, 2024	Nov 22, 2021

HGVS

Nucleotide	Protein	Molecular consequence
NM_001368894.2:c.959-3C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_000280.6:c.917-3C>G		intron variant
NM_001127612.3:c.917-3C>G		intron variant
NM_001258462.3:c.959-3C>G		intron variant
NM_001258463.2:c.959-3C>G		intron variant
NM_001258464.2:c.917-3C>G		intron variant
NM_001258465.3:c.917-3C>G		intron variant
NM_001310158.2:c.959-3C>G		intron variant
NM_001310159.1:c.917-3C>G		intron variant
NM_001310160.2:c.509-3C>G		intron variant
NM_001310161.3:c.509-3C>G		intron variant
NM_001368887.2:c.917-3C>G		intron variant
NM_001368888.2:c.917-3C>G		intron variant
NM_001368889.2:c.917-3C>G		intron variant
NM_001368890.2:c.917-3C>G		intron variant
NM_001368891.2:c.917-3C>G		intron variant
NM_001368892.2:c.959-3C>G		intron variant
NM_001368893.2:c.959-3C>G		intron variant
NM_001368899.2:c.509-3C>G		intron variant
NM_001368900.2:c.509-3C>G		intron variant
NM_001368901.2:c.509-3C>G		intron variant
NM_001368902.2:c.509-3C>G		intron variant
NM_001368903.2:c.509-3C>G		intron variant
NM_001368904.2:c.509-3C>G		intron variant
NM_001368905.2:c.509-3C>G		intron variant
NM_001368906.2:c.509-3C>G		intron variant
NM_001368907.2:c.509-3C>G		intron variant
NM_001368908.2:c.509-3C>G		intron variant
NM_001368909.2:c.509-3C>G		intron variant
NM_001368910.2:c.1160-3C>G		intron variant
NM_001368911.2:c.962-3C>G		intron variant
NM_001368912.2:c.959-3C>G		intron variant
NM_001368913.2:c.959-3C>G		intron variant
NM_001368914.2:c.959-3C>G		intron variant
NM_001368915.2:c.917-3C>G		intron variant
NM_001368916.2:c.917-3C>G		intron variant
NM_001368917.2:c.917-3C>G		intron variant
NM_001368918.2:c.1034-3C>G		intron variant
NM_001368919.2:c.1034-3C>G		intron variant
NM_001368920.2:c.992-3C>G		intron variant
NM_001368921.2:c.758-3C>G		intron variant
NM_001368922.2:c.758-3C>G		intron variant
NM_001368923.2:c.758-3C>G		intron variant
NM_001368924.2:c.758-3C>G		intron variant
NM_001368925.2:c.758-3C>G		intron variant
NM_001368926.2:c.758-3C>G		intron variant
NM_001368927.2:c.758-3C>G		intron variant
NM_001368928.2:c.716-3C>G		intron variant
NM_001368929.2:c.509-3C>G		intron variant
NM_001368930.2:c.314-3C>G		intron variant
NM_001604.6:c.959-3C>G		intron variant
NC_000011.10:g.31793556G>C
NC_000011.9:g.31815104G>C
NG_008679.1:g.29406C>G
LRG_720:g.29406C>G
LRG_720t1:c.917-3C>G

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000011.10:31793555:G:C

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: CA16606306 dbSNP: rs1057523821 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	Oct 25, 2016	RCV000423209.1
Aniridia 1 Irido-corneo-trabecular dysgenesis	Likely pathogenic (1)	criteria provided, single submitter	Nov 22, 2021	RCV001865384.4

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 (Oct 25, 2016)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000533435.4 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Comment: The c.917-3 C>G splice site variant in the PAX6 gene destroys the splice acceptor site in intron 10. It is predicted to cause abnormal gene … (more) The c.917-3 C>G splice site variant in the PAX6 gene destroys the splice acceptor site in intron 10. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.917-3 C>G variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Although this pathogenic variant has not been previously reported to our knowledge, we consider it to be pathogenic. (less)
Likely pathogenic (Nov 22, 2021)	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: SCV002277401.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 28, 2024	Publications: PubMed (2) PubMed: 17576681‚ 9536098 Comment: In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has … (more) In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 390567). This variant has been observed in individual(s) with PAX6-related conditions (Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 10 of the PAX6 gene. It does not directly change the encoded amino acid sequence of the PAX6 protein. It affects a nucleotide within the consensus splice site. (less)

Comment:

The c.917-3 C>G splice site variant in the PAX6 gene destroys the splice acceptor site in intron 10. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.917-3 C>G variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Although this pathogenic variant has not been previously reported to our knowledge, we consider it to be pathogenic.

Comment:

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 390567). This variant has been observed in individual(s) with PAX6-related conditions (Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 10 of the PAX6 gene. It does not directly change the encoded amino acid sequence of the PAX6 protein. It affects a nucleotide within the consensus splice site.

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
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.	Buratti E	Nucleic acids research	2007	PMID: 17576681
Statistical features of human exons and their flanking regions.	Zhang MQ	Human molecular genetics	1998	PMID: 9536098

Text-mined citations for rs1057523821 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_001368894.2(PAX6):c.959-3C>G

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1057523821 ...