GCM2

Chr 6ADAR

GCM transcription factor 2

Also known as: FIH2, GCMB, HRPT4, hGCMb

NCBI Gene: 9247 ENSG00000124827 UniProt: O75603 OMIM: 603716

This transcription factor serves as a master regulator of parathyroid gland development and controls parathyroid hormone expression and secretion in response to calcium levels. Mutations cause familial isolated hypoparathyroidism and hyperparathyroidism, with both autosomal dominant and autosomal recessive inheritance patterns reported. The gene shows low constraint against loss-of-function variants (pLI 0.0009, LOEUF 0.796), suggesting tolerance to complete gene loss in the general population.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene is a homolog of the Drosophila glial cells missing gene, which is thought to act as a binary switch between neuronal and glial cell determination. The protein encoded by this gene contains a conserved N-terminal GCM motif that has DNA-binding activity. The protein is a transcription factor that acts as a master regulator of parathyroid development. It has been suggested that this transcription factor might mediate the effect of calcium on parathyroid hormone expression and secretion in parathyroid cells. Mutations in this gene are associated with hypoparathyroidism. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismAD/ARLOEUF 0.802 OMIM phenotypes

Clinical Summary— GCM2

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.80LOEUF

pLI 0.001

Z-score 2.21

OE 0.44 (0.26–0.80)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.68Z-score

OE missense 0.89 (0.80–0.98)

246 obs / 277.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.44 (0.26–0.80)

0≤0.351.4

Missense OE?0.89 (0.80–0.98)

0≤0.61.4

Synonymous OE?0.96

0≤1.21.6

LoF obs/exp: 8 / 18.1Missense obs/exp: 246 / 277.7Syn Z: 0.34

This gene — mechanism propensity

0.5967th %ile

GOF

0.3391th %ile

LOF

0.51top 25%

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DN1 literature citation

GOF1 literature citation

Literature Evidence

DNMost cases of autosomal dominant isolated hypoparathyroidism are caused by gain-of-function mutations in CASR or GNA11 or dominant negative mutations in GCM2 or PTH.1

GOFMost cases of autosomal dominant hypoparathyroidism (ADH) are caused by gain-of-function mutations in CASR or dominant inhibitor mutations in GCM2 or PTH.2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References