11-31794705-G-A

Position:

• chr11-31794705-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001368894.2(PAX6):​c.649C>T​(p.Arg217*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PAX6 NM_001368894.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 2.43

Genes affected

PAX6 (HGNC:8620): (paired box 6) This gene encodes paired box protein Pax-6, one of many human homologs of the Drosophila melanogaster gene prd. In addition to a conserved paired box domain, a hallmark feature of this gene family, the encoded protein also contains a homeobox domain. Both domains are known to bind DNA and function as regulators of gene transcription. Activity of this protein is key in the development of neural tissues, particularly the eye. This gene is regulated by multiple enhancers located up to hundreds of kilobases distant from this locus. Mutations in this gene or in the enhancer regions can cause ocular disorders such as aniridia and Peter's anomaly. Use of alternate promoters and alternative splicing results in multiple transcript variants encoding different isoforms. Interestingly, inclusion of a particular alternate coding exon has been shown to increase the length of the paired box domain and alter its DNA binding specificity. Consequently, isoforms that carry the shorter paired box domain regulate a different set of genes compared to the isoforms carrying the longer paired box domain. [provided by RefSeq, Mar 2019]

PAX6 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-31794705-G-A is Pathogenic according to our data. Variant chr11-31794705-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 3466.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAX6	NM_001368894.2	c.649C>T	p.Arg217*	stop_gained	9/14	ENST00000640368.2	NP_001355823.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAX6	ENST00000640368.2	c.649C>T	p.Arg217*	stop_gained	9/14	5	NM_001368894.2	ENSP00000492024.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Aniridia 1 Pathogenic:4

Pathogenic, no assertion criteria provided	research	Laboratory of Genetic Epidemiology, Research Centre for Medical Genetics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Wessex Regional Genetics Laboratory, Salisbury District Hospital	Aug 15, 2019	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1995	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Feb 07, 2018	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 08, 2022	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 at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27463523, 24390526, 22171686, 25525159, 7550230, 12552561, 29618921, 29901133, 28321846, 32360764, 10887930, 34101622, 27535533) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 29, 2013	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 26, 2024

The c.607C>T (p.R203*) alteration, located in exon 8 (coding exon 5) of the PAX6 gene, consists of a C to T substitution at nucleotide position 607. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 203. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant was identified in multiple individuals with features consistent with PAX6-related ophthalmological disorder and segregated with disease in at least one family (Cross, 2020; Daruich, 2022; Dubey, 2015; Kuchalska, 2023; Moon, 2021; Souzeau, 2018; Syrimis, 2018; Zucco, 2024). This variant has been determined to be the result of a de novo mutation in at least one individual with features consistent with PAX6-related ophthalmological disorder (Cross, 2020). Based on the available evidence, this alteration is classified as pathogenic. -

Aniridia 1;C0344559:Irido-corneo-trabecular dysgenesis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 11, 2022

This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 3466). This variant is also known as c.649C>T; p.Arg217_x0001_*. This premature translational stop signal has been observed in individual(s) with aniridia, and microphthalmia with late-onset keratitis and iris coloboma and aniridia with slightly impaired pituitary function (PMID: 10887930, 22171686, 24390526, 27463523). It has also been observed to segregate with disease in related individuals. This sequence change creates a premature translational stop signal (p.Arg203*) 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.94	D
Vest4		0.89
GERP RS		4.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121907916; hg19: chr11-31816253; COSMIC: COSV53792293; COSMIC: COSV53792293;