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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

The GNRHR gene encodes the receptor for type 1 gonadotropin-releasing hormone. Variants in this gene are strongly associated with autosomal recessive hypogonadotropic hypogonadism 7 with or without anosmia (GenCC; PMID: 12568864, 22745237, 30947225, 34198905, 35133534). This is a relatively rare (1-9/100,000) autosomal recessive disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic-pituitary axis (OMIM #146110, Orphannet). Sensorineural hearing loss is rarely reported as associated with this syndrome (OMIM #146110).