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CACNA1A Gene Curation

CACNA1A Gene Curation

Owned by Andrea Oza
Last updated: 2024-04-10
4 min read

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

Did not curate:

  • CACNA1A related developmental and epileptic encephalopathy

  • Episodic ataxia, type 2

  • Migraine, familial hemiplegic, 1

Disease

Spinocerebellar Ataxia Type 6

Disease

Spinocerebellar Ataxia Type 6

Inheritance

Autosomal dominant

Prevalence

Orphanet

Medline Plus Genetics

 1-9 / 1 000 000 (orphanet)

Source:

Rapid or full curation?

Rapid
Full

ClinGen / GenCC / BabySeq / HGMD / OMIM

ClinGen: none. GenCC : strong (Ambry, England genomic panel App); supportive (orphanet); BabySeq: no curations for SCA; HGMD : missense and repeat variations reported
OMIM: 183086

Clinical Validity Scoring Notes and points

8988170 (Zhuchenko et al. 1997)
Case-control study compared genotyping of 475 unaffected and 173 affected (not related) individuals. 8 expansions observed in affected group, 0 observed in unaffected (p<10^-5). Unaffected alleles ranged from 4-16 repeats. In the ataxia patients, the repeats ranged from 7-27 repeats. Table 1 shows a clear grouping of the alleles between the two groups, and 8 patients with ataxia had 21-27 repeats with no controls having repeats at this size. (8x0.5 points = 4 VARIANT points). 4 probands with affected family members were also evaluated for segregation among those with expanded alleles. 21 family members were tested, 14 were affected, segregated in an autosomal dominant manner. Inverse correlation between expansion size and age of onset. LOD sum 5.08 3 POINTS SEGREGATION. Largest normal allele 16 repeats, smallest expanded allele 21.

9259275 (Reiss et al. 1997) 248 80+ year olds healthy, no fhx of neurologic disease, identified largest unaffected expansion up to 18 CAGs. 733 (3-80 y/o) affected (idiopathic sporadic progressive ataxia) individuals, patients with alternate causes or expansions in SCA1-3 genes or Friedreich's ataxia were excluded. Identified 4 with repeat expansions (22-23), retrospective fhx could not rule out parental affected status for 3, but generally no fhx. Also evaluated cohort of patients with AD SCA - Identified 28 patients from 19 families with AD SCA that had the expansion (ranging from 22-28 repeats). 19x0.5 points = 9.5 VARIANT points. Largest normal allele 18 repeats, smallest expanded allele 22.

(Yabe et al. 1997 9559993) Cohort of individuals with spinocerebellar ataxia. Expansions found in 12 of 23 families with AD SCA and 12 additional probands; 47 affected individuals and 9 at risk individuals had the expansion. Expansions ranged from 21-33 repeats. Age of onset 19-69 with inverse correlation between age and repeat size. No expansion seen in repeat size through generations. Normal controls had 4-18 repeats.

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

Loss of function / Gain of function / Dominant Negative

Repeat expansions -

Normal ≤18 CAG repeats

Uncertain - 19 CAG repeats

Full penetrance 20-33

Cutoff - 19

Citations: PMID: 9559993, 9879686, 9302278, 9259275, 8988170

 

(I agreed with the GeneReviews allele categorizations after quickly reviewing the citations they used and the papers cited in clinical validity scoring above)

  • GeneReviews: Normal alleles. ≤18 CAG repeats [Shizuka et al 1998 PMID: 9879686]. Full-penetrance alleles. 20-33 CAG repeats [Jodice et al 1997 PMID: 9302278, Yabe et al 1998 PMID: 9559993]. Asymptomatic individuals bearing an expansion of (CAG)20 or greater are expected to develop symptoms at some time in their life. The most common pathogenic allele has 22 CAG repeats. Alleles of questionable significance. 19 CAG repeats.

  • GnomAD - very few alleles >19 repeats

  • Mayo’s cutoff is 19https://docs.google.com/spreadsheets/d/189Ph82ZPDhHwgTtmmPpCItan8boniGIL/edit#gid=1020718149

Penetrance

Complete (100%)

High (≥80%)

Moderate  (<80% and >20%)

Low (≤20%)

(list source/PMID)

 

Age of Onset

Congenital

Pediatric

Adolescent

Adulthood

Late adulthood

(list source/PMID)

 

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

 

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

- 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 04/10/2024 https://broadinstitute.atlassian.net/browse/BCL-168

 

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