Inheritance

Autosomal dominant

Prevalence

 The prevalence of microphthalmia is 1:7,000, anophthalmia is 1:30,000 and coloboma is 1:5,000 live births, with combined prevalence 3-30:100,000 births. Associated malformations affect 32-93% of the patients. There is no clear predilection for ethnicity or gender.

Source: ORPHA:2542

Rapid or full curation?

ClinGen / GenCC / BabySeq / HGMD / OMIM

No clingen curations. Limited in GenCC (Ambry and Invitae), no BabySeq curations. REVEL: 0.272.

Clinical Validity Scoring Notes and points

c.4G>A p.V2M - (0.0002475, 26/73446 AA chr in gAD v4)

• PMID: 27391121 - variant found in patient who also harbored c.904C>G p.L302V (0.1%, 116/75036 w/ 1 HOM in African/African american); however, they also had a variant in CHD7. Clinical features: Autism, subtle microphthalmia, and repetitive hand movements…Father had small eyes and was heterozygous for both changes.” Not scoring any points for either variant, too common for AD disease and phenotype could be due to CHD7 variant.

c.169G>A p.A57T - 0.1%, 118/90724 South Asian chr and 2 homozygotes.

• 22226084 - Variant does segregate per fig 1, but it is too common to cause this disease. 7 affected segregations. In human cell lines, ABCB6 expression in retnal and RPE cells was higher than other tissues per the text (but I’m really not seeing this in fig 3), maybe RPE I see a faint line. Zebrafish morpholino knockdown, abcb6 transcripts expressed in the CNS and eyes, and around the lens. They also showed a keyhole like shape of the pupil (fig 5). FXNL EVIDENCE, scoring 0.5 points for zebrafish knockdown.

30653986 - supplement mmc4 shows several variants - but none are worth any points.

• 575G>A Arg192Gln (B/LB in ClinVar due to MAF, 0.4% grpmax) no points.

• c.1006C>T p.R336W - 0.00007236 10/74838 African/AFrican Amer chr in gAD v4. REVEL: 0.681. present in unaffected mother. not scoring any points.

• c.826C>Tp.Arg276Trp - benign in ClinVar, 1.4% and 19392 alleles in gnomAD.

• c.1562C>G p.Thr521Ser - B/LB in ClinVar, 1.6% in ClinVar

Clinical Validity Points Total

0.5 points (being generous)

Clinical Validity Classification

Limited

Source:

Molecular Mechanism

Loss of function / Gain of function / Dominant Negative

Penetrance

(list source/PMID)

Source:

Age of Onset

(list source/PMID)

Severity

Clinical Features

Sources:

HPO Terms

https://hpo.jax.org/app/

Gene SOPs & Notes

 LINK if SOP is a long document. Short notes if it is easy to digest. eg. Last known truncating variant

Curation Summary

Case ID, Curator name, Date, Jira ticket link

Andrea Oza 01.18.24 D-171018974-BH-4046-P-A