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

Disease

CNBP-related myotonic dystrophy

Inheritance

Autosomal dominant

Prevalence

 1-9 / 100 000

Source:ORPHA:606

Rapid or full curation?

  • Rapid
  • Full

ClinGen / GenCC / BabySeq / HGMD / OMIM

ClinGen - none. GenCC - Strong (Invitae), BabySeq - none. HGMD - 1 entry for repeat expansions.

Clinical Validity Scoring Notes and points

Liquori 2001 (PMID: 11486088) - mapped the MD2 locus and used positional cloning to identify the DM2 mutation. Per text, all 51 affected individuals in 6 DM2 families were found to have expanded alleles. Sequencing revealed a complex repeat motif ( TG)n( TCTG)n(CCTG)n. In controls this tract ranged from 104-176 basepairs. The largest repeat tract in normal controls had 26 CCTG repeats with two interruptions. Three families with a total of 6 individuals with expansions of the CCTG repeat (fig 1D). Expanded alleles ranged from 75-1100 CCTG repeats (>10 individuals shown here 0.5x10 variant points). The normal alleles.

Source:

Clinical Validity Points Total

Source:

Clinical Validity Classification

 Classifications (pts)

Definitive (12pts)

Strong (12pts)

Moderate (7-11pts)

Limited (0.1-6pts)

No genetic evidence

Refuted

Disputed

Source:

Molecular Mechanism

 Mechanisms

Loss of function

Gain of function

Dominant negative

Unknown

Other

Loss of function / Gain of function / Dominant Negative

Triplet Repeat expansion - complex motif (TG)n(TCTG)n(CCTG)n

Literature:

  • GeneReviews PMID: 20301639 - normal ≤30 uninterrupted CCTG repeats OR 11-26 CCTG repeats with any GCTC or TCTG interruptions. Unknown significance (normal vs. mutable) 27-29 CCTG repeats. Mutable normal (premutatio) ~30-~54 CCTG repeats. Unknown significance (premutation vs pathogenic) ~55-74 ~55-74 CCTG repeats. Pathogenic ~75-11,000 CCTG repeats.

  • gnomAD Normal ≤ 54, Pathogenic ≥ 55

  • Stripy - normal ≤29, intermediate 30-55, pathogenic ≥55

  • Not in the Mayo paper https://docs.google.com/spreadsheets/d/189Ph82ZPDhHwgTtmmPpCItan8boniGIL/edit#gid=1020718149

  • Other labs:

    • labcorp - pathogenic is over 75. Athena - Normal: Less than 177 base pairs. Mayo (sends to Athena). Sample report shows Normal (<177 base pairs), Borderline (177-372 base pairs), Positive (>372 base pairs) Fulgent, not provided. GeneDx - Normal alleles have 26 or less CCTG repeats and disease alleles have 75 or more repeats. Disease alleles can contain more than 11,000 repeats, with an average of 5,000 repeats.1

  • INTERRUPTIONS:

    • Large uninterrupted repeat lengths have decreased stability.

Penetrance

 options

Complete (100%)

High (≥80%)

Moderate  (<80% and >20%)

Low (≤20%)

(list source/PMID)

Source:

Age of Onset

 options

Congenital

Pediatric

Adolescent

Adulthood

Late adulthood

(list source/PMID)

Severity

 Options

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

 Examples

- 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

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