Familial hyperparathyroidism or hypocalciuric hypercalcaemia
Gene: GCM2
Only literature reports are from one group (Guan et al 2016 PMID: 27745835and Guan et al 2017 PMID: 29264504). Frequency of p.(Tyr394Ser) (detected in 5 families) is high in GnomAD (174/282870, 1/812 heterozygotes; Ashkenazi Jew: 134/10370, 1/40 heterozygotes, 2 homozygotes). Needs confirmation by other groups before inclusion in panel. Suggest downgrade to amber pending further evidence.Created: 16 Jan 2019, noon
Publications
Gain of function variants in the CCID domain of GCM2 (codons 379-394) have been reported in association with hyperparathyroidism. Published data includes >3familes and functional studies have been undertaken, thus fulfilling the criteria for green gene. However, publications to date have been from a single group although PMID: 29199197 is a second group seemingly corroborating the first; this is an abstract from a meeting and has not yet been published under peer review to my knowledge. We have included this gene in diagnostic screening and have >3 families with variants in this region, segregation studies have not been possible and so to date (Jan 2019) we have been a little conservative in reporting, considering variants likely to be pathogenic rather than of proven pathogenicity.Created: 9 Jan 2019, 5:37 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
hyperparathyroidism; hypoparathyroidism
Publications
Mode of pathogenicity
Other
Variants in this GENE are reported as part of current diagnostic practice
The rating of this gene has been updated following NHS Genomic Medicine Service approval.Created: 3 Mar 2022, 1:44 p.m. | Last Modified: 3 Mar 2022, 1:44 p.m.
Panel Version: 2.16
Looking at the available evidence, there is an additional paper (PMID 31671402) reporting on the same variant that was detected previously by Guan et al 2016 and 2017. This gene is recommended to be promoted to Green at the next review.
This gene was proposed to be given Green status by Soo-Mi Park (East Anglian Medical Genetics Service).Created: 28 Jan 2021, 10:16 a.m. | Last Modified: 28 Jan 2021, 10:18 a.m.
Panel Version: 2.6
Comment when marking as ready: Comment on list classification: As discussed in the GMS Endocrinology Specialist Test Group webex call 28th Jan 2019: The Specialist Test Group agreed that there is insufficient evidence to rate this gene as green. So demoted from green to amber.Created: 29 Jan 2019, 11:54 a.m.
Comment on list classification: Promoted from red to green based on below comment.Created: 5 Dec 2018, 2:24 p.m.
GCM2 is confirmed to be associated with hyperparathyroidism 4 in OMIM but no phenotypes are listed in Gene2Phenotype. GCM2 is also a green gene in the Familial hypoparathyroidism (Version 1.7). There are 3 unrelated cases of patients with hyperparathyroidism who have different variants in GCM2. Variants in GCM2 cause gain-of-function effects.Created: 5 Dec 2018, 2:24 p.m.
Publications
Mode of pathogenicity
Other
Tag for-review was removed from gene: GCM2.
Source Expert Review Green was added to GCM2. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Tag for-review tag was added to gene: GCM2.
Publications for gene: GCM2 were set to 27745835; 29264504; 14715834; 29199197
Ivone Leong: GCM2 is confirmed to be associ
Gene: gcm2 has been classified as Amber List (Moderate Evidence).
Gene: gcm2 has been classified as Amber List (Moderate Evidence).
Publications for gene: GCM2 were set to 27745835; 29264504; 14715834
Gene: gcm2 has been classified as Green List (High Evidence).
Gene: gcm2 has been classified as Green List (High Evidence).
Publications for gene: GCM2 were set to 27745835; 29264504
gene: GCM2 was added gene: GCM2 was added to Familial hyperparathyroidism. Sources: Radboud University Medical Center, Nijmegen,Literature Mode of inheritance for gene: GCM2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: GCM2 were set to 27745835; 29264504 Phenotypes for gene: GCM2 were set to Hypoparathyroidism, familial isolated (146200); Hyperparathyroidism 4 (617343)