Inheritance

Autosomal dominant

Prevalence

Rare. 11 affected individuals described.

Source: PMID: 35051358

Rapid or full curation?

ClinGen / GenCC / BabySeq / HGMD / OMIM

Clinical Validity Scoring Notes and points

Variant/Case Evidence:

All information below is from PMID: 35051358

c.34C>A p.Pro12Thr: Individual 1 in table 1. De novo on trio exome. Variant is absent in v4. Unable to rescue H2AK119ub WT levels in a BAP1 knockout cell line. Unable to rescue expression of TMSB4X and S100A11 which is regulated by BAP1. Authors looked at T cells from the affected individual and showed that the steady-state level of Ub-H2A was substantially increased in cells of the affected children when compared to those of their respective related controls. (0.6pts +0.5pts for functional evidence)

c.34C>G p.Pro12Ala: Individual 2 in table 1. De novo on trio exome. Variant is absent in v4. Rescued H2AK119ub WT levels in a BAP1 knockout cell line to near normal, suggesting enzyme activity BUT unable to rescue expression of TMSB4X and S100A11 which is regulated by BAP1 (0.6pts + 0.25pts for functional studies)

• This variant is also referenced in PubMed: 38091987 but it is not a new case report.

c.91G>A p.Glu31Lys: Individual 3 in table 1. De novo on trio exome. Variant is absent in v4. (0.6pts)

c.146T>C p.Leu49Pro: Individual 4 in table 1. De novo on trio exome. Variant is absent in v4. (0.6pts)

c.272G>C p.Cys91Ser: Individual 5 in table 1. De novo on trio exome. Variant is absent in v4. Unable to rescue H2AK119ub WT levels in a BAP1 knockout cell line. Unable to rescue expression of TMSB4X and S100A11 which is regulated by BAP1. Authors looked at T cells from the affected individual and showed that the steady-state level of Ub-H2A was substantially increased in cells of the affected children when compared to those of their respective related controls. (0.6pts +0.5pts for functional evidence)

c.271T>G p.Cys91Gly: Individual 6 in table 1. De novo on trio exome. Variant is absent in v4. (0.6pts)

c.271T>C p.Cys91Arg: Individual 7 and individual 8 in table 1. De novo on trio exome in both. Variant is absent in v4. Unable to rescue H2AK119ub WT levels in a BAP1 knockout cell line. Unable to rescue expression of TMSB4X and S100A11 which is regulated by BAP1. (1.2pts +0.5pts for functional evidence)

c.506A>G p.His169Arg: Individual 9 and 10 in table 1. De novo on trio exome in both. Variant is absent in v4. Unable to rescue H2AK119ub WT levels in a BAP1 knockout cell line. Unable to rescue expression of TMSB4X and S100A11 which is regulated by BAP1. (1.2pts +0.5pts for functional evidence)

c.2153G>A p.Arg718Gln: Individual 11 in table 1. De novo on trio exome + genome. Present in 3 hets in v4. Rescued H2AK119ub WT levels in a BAP1 knockout cell line to near normal, suggesting enzyme activity. Expression of TMSB4X and S100A11 also indistinguishable from WT rescue. (0pts due to AF and fn evidence indistinguishable from WT)

Segregation Evidence: none

Case/Control Evidence: none

Experimental Evidence: none (see variant-level functional evidence above).

Clinical Validity Points Total

8.25

Clinical Validity Classification

MODERATE

Molecular Mechanism

Loss of function

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

https://docs.google.com/document/d/1XY2_T3IJ7mtVPSrC6dCWmV2gqgqJ2p1laVBGZySK7vM/edit

Curation Summary

The BAP1 gene is associated with autosomal dominant Kury-Isidor syndrome, which is characterized by speech and motor delay, hypotonia, seizures, growth failure, and dysmorphic facial features. Some individuals have abnormalities of the hands, feet, spine, heart, eye, or kidneys/urogenital system. The severity of the disorder is highly variable, The BAP1 gene has also been associated with autosomal dominant BAP1-related tumor predisposition syndrome, which is characterized by an increased risk for BAP1-inactivated melanocytic tumors and several cancers. There is currently no evidence suggesting that individuals at risk for autosomal dominant Kury-Isidor syndrome are at risk for BAP1-inactivated melanocytic tumors and several cancers, or vice versa.

Case ID, Curator name, Date, Jira ticket link

Areesha Salman, 9/24/24. SDSM-2KG.