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NOP56 Gene Curation

NOP56 Gene Curation

Owned by Andrea Oza
2024-05-13
3 min read

Gene-disease assertions not curated here (add link or write note):

Disease

Spinocerebellar ataxia 36

Disease

Spinocerebellar ataxia 36

Inheritance

Autosomal dominant

Prevalence

Orphanet

Medline Plus Genetics

 

Source:

Rapid or full curation?

Rapid
Full

ClinGen / GenCC / BabySeq / HGMD / OMIM

ClinGen - none. GenCC - Definitive (Ambry), Strong (Invitae)

Clinical Validity Scoring Notes and points

Kobayashi 2011 PMID: 21683323

  • Linkage in 3 unrelated Japanese families (LOD of 4.6) mapped to the gene. Expansion showed complete segregation.

  • Repeat sizes ranged from 3 to 8 in 300 Japanese controls

  • Cases had expansions that were no smaller than 1500 repeats (see supplement), Expansions ranged from approximately 1500-2500 in 27 cases.

  • No association between length of repeat and age of onset, no obvious anticipation observed in the pedigrees.

  • Decreased expression in spinal tissue observed. Immunoblotting confirmed the presence of Nop56 in neural tissues.

  • Patients RNA expression and protein levels appeared normal in LCLs, indicating that haploinsufficiency is not the mechanism.

  • Proposed toxic gain of function

Lam 2023 PMID: 37810464

  • Analyzed 1257 British patients with hereditary ataxia and 7506 controls.

  • Normal alleles 3-14 hexanucleotide repeats

  • Expanded alleles range from 30-2500 (most between 650 and 2500). It isn’t 100% clear what the smallest expanded allele is so I would use 650.

 

Baviera-Munoz 2023 PMID: 37332636\

  • NOP56 expansion identified in 37 individuals from 16 apparently unrelated families from a Spanish cohort with cerebellar ataxia.

  • Not clear what the size of the expansions are.

Wang 2022 pMID: 36368168

  • Case report and review. Cites normal range as 3-14 repeats. Expanded as 650-2500.

  • Case report here describes expanded allele in this family as 782 repeats

 

Source:

Clinical Validity Points Total

 

Source:

Clinical Validity Classification

Definitive (12pts)

Strong (12pts)

Moderate (7-11pts)

Limited (0.1-6pts)

No genetic evidence

Refuted

Disputed

 

Source:

Molecular Mechanism

Loss of function

Gain of function

Dominant negative

Unknown

Other

 

Short Tandem Repeat - GGCCTG in intron 1

  • Normal ≤ 14

  • Pathogenic ≥ 650

Cutoff: 15

PMID: 21683323, 37810464

 

Review:

  • STRchive - Normal: 3-14, Intermediate 15-649, Pathogenic 650-2500

  • GnomAD - Normal ≤ 14, Pathogenic ≥ 650

  • Nirvana - Normal 0-14, Expanded 15-inf

  • STRipy - Normal 3-14, Pathogenic ≥25

  • Mayo - not available

Penetrance

Complete (100%)

High (≥80%)

Moderate  (<80% and >20%)

Low (≤20%)

(list source/PMID)

 

Source:

Age of Onset

Congenital

Pediatric

Adolescent

Adulthood

Late adulthood

(list source/PMID)

Average in the 5th or 6th decade (PMID: 37810464)

Severity

Embryonic lethal - presence of a pathogenic variant or variants is not compatible with life. The penetrance must be complete.
Severe - presence of a pathogenic variant or variant(s) results in significantly reduced fitness. The penetrance must be complete or high.
Moderate - significant morbidity or mortality due to clinical features, but fitness may not be reduced, or penetrance is reduced.
Mild - Presence of a variant or variant(s) is not associated with reduced fitness, no significant morbidity or mortality, and/or penetrance is low.
None - presence of a variant results in no phenotype. An example is recessive disorders in which no phenotype is reported in carriers.

 

Clinical Features

Cerebellar ataxia

  • Dysarthria, dysphagia, vertigo, upper and lower motor neuron signs

Cerebellar atrophy

Hearing loss

Sources: 37810464, 37332636

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

- The @GENE@ is associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs).

- Variable expression or severity:
The severity and expressivity of the disorder is highly variable, even within families.
- If multiple conditions associated with the gene:
It has also been associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs).

- Limited evidence gene: The PCNA gene has been reported in individuals with early onset autosomal recessive ataxia (PMID: 33426167, 24911150), however, evidence supporting this gene-dIsease relationship is limited

 

Case ID, Curator name, Date, Jira ticket link

Andrea Oza 05.13.24 https://broadinstitute.atlassian.net/browse/BCL-168

 

 

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