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DLC1 Gene Curation

DLC1 Gene Curation

Owned by Andrea Oza
2024-04-03
3 min read

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

Disease

CONGENITAL HEART DEFECTS

Disease

CONGENITAL HEART DEFECTS

Inheritance

autosomal dominant

Prevalence

Orphanet

Medline Plus Genetics

 COMMON

Source:

Rapid or full curation?

Rapid
Full

ClinGen / GenCC / BabySeq / HGMD / OMIM

No ClinGen curations, limited for CHD by Ambry, limited by BabySeq (cites 24587289, 24476948). HGMD papers listed in clinical validity.

Clinical Validity Scoring Notes and points

  • 24587289 - see table 1 for list of variants. Instead of scoring all of these, assuming they all would get their full points, we would only reach 1.3 variant points since this is a rare condition and they are al VUS (0.1x13). Fig 2 does not show convincing evidence that any of the variants overexpressed behaved differently than WT in cell migration (possibly mut 2, 4 and 5 which correspond to Mutant 2, Met360Lys, ; Mutant 4, Glu418Lys; Mutant 5, Asp554Val). fig 3c shows Glu418Lys localizes to both cytoplasm and nucleus. So another 0.5 variant points. 1.8 points total

    image-20240403-191523.png

  • 32368696 - part of WAVE2 complex. c.4154T>C p.L1385P listed as de novo in case w/ LVOs. Absent gnomAD. 0.6 points.

PMID: 15710412 - Homozygous null mouse model is embryonic lethal and the heart is incompletely developed. Adult het mice did not display any abnormaliites. Doesn’t match proposed inheritance, but scoring some evidence for the abnormal heart development. 0.5 point.

PMID: 20199662 - Another mouse model homozygous gene trapped (targets 1 isoform) embryos showed defects in the brain, heart, and placental blood vessels. 0.5 point.

Paper in biorxiv from 2021 (: https://doi.org/10.1101/2021.02.11.430763;) indicate dlc1 is important for vascular development in zebrafish. Loss of dlc1 (dlc1 null embryos) negatively affected the lumenization of the first aortic arch arteries and the lateral 9 dorsal aortae. Since animals are null, scoring as 0.5 point animal model

Source:

Clinical Validity Points Total

4.4 points

Source:

Clinical Validity Classification

Definitive (12pts)

Strong (12pts)

Moderate (7-11pts)

Limited (0.1-6pts)

No genetic evidence

Refuted

Disputed

Limited.

Source:

Molecular Mechanism

Loss of function

Gain of function

Dominant negative

Unknown

Other

Loss of function / Gain of function / Dominant Negative

 

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)

 

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

 

 

 

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