Inheritance

Autosomal recessive

Prevalence

 1-9 / 1 000 000

Source: Orphanet

Rapid or full curation?

ClinGen / GenCC / BabySeq / HGMD / OMIM

1 ClinGen classification (Limited - 1/25/2017)

Ambry has classified this gene as Moderate (8/31/2018) and Invitae has classified it as Strong (2/7/2020)

Clinical Validity Scoring Notes and points

Variant/Case Evidence:

PMID: 18523010

• 4 relevant NHP2 variants identified in dyskeratosis congenita patients (3 missense variants, 1 nonsense variant predicted to give rise to an elongated protein) -

• Ala118Thr variant was heterozygous, Tyr139His was homozygous, Val126Met and X154ArgextX*52 were compound heterozygous

• 0.1 + 0.1 + 0.1 + 0.5 = 0.8 pts

PMID: 36943377

• 2 NHP2 variants identified in a patient with dyskeratosis congenita: p.P37R and p.E89K

• P37R is absent from gnomAD, E89K is rare in gnomAD

• 0.1 + 0.1 = 0.2 pts

Segregation Evidence:

Case/Control Evidence:

Experimental Evidence:

PMID: 18523010

• NHP2 was knocked down in HeLa cells by using siRNAs against NHP2. Two independent siRNAs were highly effective, reducing NHP2 mRNA levels by >95%. This knockdown translated into significantly reduced levels of TERC at 48 and 72 h after transfection - 1 pt

• Expressed mutant and wild-type NHP2 in HeLa cells in which the endogenous NHP2 is depleted. These experiments suggest that expression of wild type NHP2 can increase TERC accumulation compared with cells with exogenous mutant NHP2 -1 pt

PMID: 11160879

• Depletion of Cbf5p, Nhp2p and Nop10p is correlated with a drastic decrease in the steady-state levels of the mature non-polyadenylated form of hTR in yeast - 1 pt

PMID: 20008900

• Immunoprecipitation showed that NHP2 binding to NOP10 is severely impaired by the Y139H mutation, showing an effect on the assembly of different H/ACA RNP populations - 1 pt

Source:

Clinical Validity Points Total

Source:

Clinical Validity Classification

5 pts (limited)

Source:

Molecular Mechanism

Loss of function (ClinGen dosage sensitivity score of 30)

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