Inheritance

Autosomal dominant

Prevalence

 <1 / 1 000 000

Source: Orphanet

Rapid or full curation?

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

Definitive

Source: 16138911, 10581021, 31190316, 38227102

Molecular Mechanism

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

(list source/PMID)

Source:

Age of Onset

(list source/PMID)

Severity

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

Case ID, Curator name, Date, Jira ticket link

Andrea Oza 05.21.2024 https://broadinstitute.atlassian.net/browse/BCL-168