Submissions for variant NM_001368894.2(PAX6):c.1310A>T (p.Ter437Leu)

dbSNP: rs121907922

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000327291	SCV000225770	pathogenic	not provided	2015-01-15	criteria provided, single submitter	clinical testing
GeneDx	RCV000327291	SCV000329453	pathogenic	not provided	2021-12-27	criteria provided, single submitter	clinical testing	Normal stop codon changed to a Leucine codon, leading to the addition of 14 amino acids at the C-terminus; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18494745, 20132240, 28321846, 21850189, 25555363, 22204637, 16098226, 6330922, 18494744, 16199712, 22361317, 28698011, 18241071, 10477494, 11309364, 26661695, 12552561, 27431685, 29618921, 29367200, 32360764, 33594928, 27535533, 34101622, 33726816, 32467297)
Fulgent Genetics, Fulgent Genetics	RCV000762838	SCV000893197	pathogenic	Aniridia 1; Foveal hypoplasia 1; Coloboma of optic nerve; Autosomal dominant keratitis; Isolated optic nerve hypoplasia; Irido-corneo-trabecular dysgenesis; 11p partial monosomy syndrome; Congenital ocular coloboma	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000805010	SCV000944952	pathogenic	Aniridia 1; Irido-corneo-trabecular dysgenesis	2024-10-22	criteria provided, single submitter	clinical testing	This sequence change disrupts the translational stop signal of the PAX6 mRNA. It is expected to extend the length of the PAX6 protein by 14 additional amino acid residues. This variant is not present in population databases (gnomAD no frequency). This protein extension has been observed in individual(s) with aniridia (PMID: 11309364, 12552561, 27431685, 28321846, 29618921). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this PAX6 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 10,718 individuals referred to our laboratory for PAX6 testing. This variant is also known as c.1290 A>T and X437L. ClinVar contains an entry for this variant (Variation ID: 3474). For these reasons, this variant has been classified as Pathogenic.
Wessex Regional Genetics Laboratory, Salisbury District Hospital	RCV000003642	SCV001055829	pathogenic	Aniridia 1	2019-08-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000327291	SCV001247619	pathogenic	not provided	2024-01-01	criteria provided, single submitter	clinical testing	PAX6: PP1:Strong, PM2, PM4, PS4:Moderate, PM6:Supporting, PP4
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000327291	SCV001450012	likely pathogenic	not provided	2018-03-15	criteria provided, single submitter	clinical testing
SingHealth Duke-NUS Institute of Precision Medicine	RCV005234778	SCV005881521	likely pathogenic	Foveal hypoplasia 1	2025-02-05	criteria provided, single submitter	clinical testing	Prevalence in affected patients is greater compared to the general populace (PS4). The variant extends the protein length past the stop codon (PM4). Variant is not found in gnomAD exomes or genomes (PM2). There is cosegregation with disease phenotypes in multiple families across multiple studies (PP1_str, PMID: 21850189;25555363;22361317;18241071;26661695;12552561;27431685;29618921;29367200;33594928)
OMIM	RCV000003642	SCV000023805	pathogenic	Aniridia 1	2003-02-01	no assertion criteria provided	literature only
Laboratory of Genetic Epidemiology, Research Centre for Medical Genetics	RCV000003642	SCV000584165	pathogenic	Aniridia 1		no assertion criteria provided	research
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000785745	SCV000924312	likely pathogenic	Hypertelorism; Visual impairment; Nystagmus	2018-03-29	flagged submission	clinical testing