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Katherine Lafferty

Katherine Lafferty

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

Disease

FORMAT: HEADING 1

SH2B3-related myeloproliferative neoplasms

Inheritance

Autosomal recessive / autosomal dominant / X-linked

Prevalence

Expand
titlePossible sources

Orphanet

Medline Plus Genetics

  MDS in general is about 4.4 to 4.6 cases per 100,000 people

Source: https://www.cancer.gov/types/myeloproliferative/hp/myelodysplastic-treatment-pdq

Rapid or full curation?

  •  Rapid
  •  Full

ClinGen / GenCC / BabySeq / HGMD / OMIM

Clinical Validity Scoring Notes and points

Variant/Case Evidence:

PMID 32641076 c.1A > G variant found in one individual with unexplained hemolysis by WES. This could potentially be on the spectrum of myeloproliferative disorder (1 pt)

PMID 31173385 c.1198G>A, p.E400K variant found in an individual with features of MDS/MPN-overlap syndrome. Variant present in gnomAD v4 AF=0.18% (European chromosomes) so no points given.

PMID 31102422 c.1261C>T p.Arg421Trp variant identified in individual with ALL (no points for inconsistent phenotype)

PMID 24092923 Consanguineous family with c.671insGGCCCCG p. Asp231Glyfs*38 with autoimmune disorders and acute lymphoblastic leukemia (ALL). Does not match cell lineage or inheritance patterns (no points)

Image Added

PMID 26457647- Cohort of JMML, multiple somatic in SH2B3. One germline variant p.E400K. No points due to high frequency

Segregation Evidence:

Case/Control Evidence:

Experimental Evidence:

Source:

Clinical Validity Points Total

Source:

Clinical Validity Classification

Expand
titleClassifications (pts)

Definitive (12pts)

Strong (12pts)

Moderate (7-11pts)

Limited (0.1-6pts)

No genetic evidence

Refuted

Disputed

Limited

Source:

Molecular Mechanism

Expand
titleMechanisms

Loss of function

Gain of function

Dominant negative

Unknown

Other

Loss of function / Gain of function / Dominant Negative

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

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

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