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Andrea Oza

Andrea Oza

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Disease

hypogonadotropic hypogonadism 7 with or without anosmia

Inheritance

Autosomal recessive

Prevalence

Expand
titlePossible sources

Orphanet

Medline Plus Genetics

 

Source:

Rapid or full curation?

  •  Rapid
  •  Full

ClinGen / GenCC / BabySeq / HGMD / OMIM

ClinGen - none, GenCC - strong by Invitae, BabySeq - none. HGMD scoring below

Clinical Validity Scoring Notes and points

Variants from HGMD (NM_000406.3), prioritized LOF variants for efficiency

c.2T>C p.M1? (low frequency 0.0008% in gnomAD)

  • PMID: 12568864 - variant found homozygous in an individual with hypogonadotrophic hypogonadism. Another missense was also found in the proband homozygous, but the mother was cmp het for the missense and p.M1?. 2 POINTS LOF

  • PMID: 22745237 - In table 2, proband 3, a female with nIHH was comp het with this variant and two additional variants Q106R and R139H. 2 POINTS LOF

c.112C>T p.R38*

  • PMID: 30947225 - WES performed in a family with nCHH. Variant found homozygous in an affected parent and three affected children. 3 AR SEG. 2 POINT VARIANT EVIDENCE

c.266T>A p.L89*

  • PMID: 29419413 Patient 31 with nCHH, but also had other variants. Not scoring this individual due to possible alternate causes (FGFR1)

c.342C>A p.C114*

  • PMID: 34198905 - In patient 24 - compound het with GNRHR p.R262Q (c.785G>A) with hyposmia. The missense variant has many publications in HGMD. This is a cohort of patients w/ Kallman syndrome. 2.5 POINT FOR BOTH VARIANTS

c.35delA p.(Asn12Ilefs*12)

  • PMID: 35133534 - table 2, variant in patient H200 compound het with Thr32Ala. This is a cohort of 68 nCHH patients. HEARING LOSS REPORTED IN 1 INDIVIDUAL FROM COHORT, BUT DON’T NOTE WHICH INDIVIDUAL, and there are multiple genes. 2 VARIANT POINTS FOR LOF VARIANT

Source:

Clinical Validity Points Total

at least 10.5

Source:

Clinical Validity Classification

Expand
titleClassifications (pts)

Definitive (12pts)

Strong (12pts)

Moderate (7-11pts)

Limited (0.1-6pts)

No genetic evidence

Refuted

Disputed

AT LEAST MODERATE (stopped here for efficiency sake)

Source:

Molecular Mechanism

Expand
titleMechanisms

Loss of function

Gain of function

Dominant negative

Unknown

Other

Loss of function

See clinical validity scoring, >3 LOF variants reported.

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

PMID: 23643382 - NO hearing loss reported in individuals with GNRHR

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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