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Andrea Oza

Andrea Oza

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

Disease

Spinocerebellar ataxia 12

Inheritance

Autosomal dominant

Prevalence

Expand
titlePossible sources

Orphanet

Medline Plus Genetics

 <1 / 1 000 000

Source: Orphanet

Rapid or full curation?

  •  Rapid
  •  Full

ClinGen / GenCC / BabySeq / HGMD / OMIM

ClinGen - none. GenCC - Strong (Invitae). BabySeq - none. HGMD papers below.

Clinical Validity Scoring Notes and points

Holmes 1999 PMID: 10581021

  • A large pedigree with SCA. Onset ranged from 8-55y. All 10 living affected family members had an expansion. Unexpanded alleles were <29 repeats. Expanded were >65. In 394 healthy controls, the unexpanded alleles ranged from 7-28. LOD score 4.61. 2 POINTS SEG, 0.5 VARIANT

Wang 2011 PMID: 21743138 - can’t access, DOI error.

Brusco 2004 PMID: 15148151

  • table 2, normal alleles 7-31 and pathologic 55-78. I don’t see any individuals with expansions in this gene.

Rossi 2019 PMID: 31190316 - case report with 61 CAG repeats. 0.5 VARIANT

Wan 2021 PMID: 34284285

  • All individuals in table 1 had an expanded SCA12 allele along with another expansion in another gene

Zheng 2024 PMID: 38227102

  • Family 1 One proband w/ essential tremor 51 repeats. She had additional features of SCA - staggering gait, dysarthria, brisk reflexes, ischemic lesions on MRI. Expansion segregated in affected brother. 1 SEG, 0.5 VARIANT

Bahl 2005 PMID: 16138911

  • Found that expansions in PPP2R2B account for ~16% (16/124) of AD ataxia cases in a cohort from N. India. Length of expanded allele ranges from 51-69. Describe normal alleles as 7-32 repeats. 20*0.5 = 10 points variant.

Clinical Validity Points Total

Definitive

Source: 16138911, 10581021, 31190316, 38227102

Clinical Validity Classification

Expand
titleClassifications (pts)

Definitive (12pts)

Strong (12pts)

Moderate (7-11pts)

Limited (0.1-6pts)

No genetic evidence

Refuted

Disputed

Definitive

Source: 16138911, 10581021, 31190316, 38227102

Molecular Mechanism

Expand
titleMechanisms

Loss of function

Gain of function

Dominant negative

Unknown

Other

PMID: 20533062

Short Tandem Repeat - CAG repeats in the 5’UTR

  • Normal ≤ 32

  • Pathogenic ≥51

  • Cutoff 33

Review:

  • Stripy - Normal: 7-31. Pathogenic ≥51

  • STRchive - Normal 4-32. Pathogenic ≥51

  • gnomAD Normal 4-32. Pathogenic ≥51

  • Depienne (review) PMID:33811808- Normal 4-32, pathogenic ≥43-78.

  • Nirvana annotations, Normal 0-32, Expanded 33-inf

  • Mayo - none

Penetrance

Expand
titleoptions

Complete (100%)

High (≥80%)

Moderate  (<80% and >20%)

Low (≤20%)

(list source/PMID)

Source:

Age of Onset

Expand
titleoptions

Congenital

Pediatric

Adolescent

Adulthood

Late adulthood

(list source/PMID)

Severity

Expand
titleOptions

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

Most individuals present in the fourth decade with upper extremity tremor, progressing over several decades to include head tremor, gait ataxia, dysmetria, dysdiadokinesis, hyperreflexia, paucity of movement, abnormal eye movements and, in the oldest subjects, dementia. Cortical and cerebellar atrophy on MRI/CT in some - PMID: 10581021

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

Expand
titleExamples

- 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 05.21.2024

Jira Legacy
serverSystem Jira
serverIdeee25142-2510-336f-918a-865682ebdf2e
keyBCL-168

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