LCMT1

Chr 16

leucine carboxyl methyltransferase 1

Also known as: CGI-68, LCMT, PPMT1

NCBI Gene: 51451 ENSG00000205629 UniProt: Q9UIC8 OMIM: 610286

LCMT1 encodes a methyltransferase that methylates the C-terminal leucine residue of protein phosphatase 2A catalytic subunits, which is critical for proper phosphatase regulation. Mutations cause autosomal recessive intellectual disability with variable neurological features including seizures and developmental delay. This gene shows low constraint against loss-of-function variants.

OMIM ResearchSummary from RefSeq, UniProt

LCMT1 catalyzes the methylation of the carboxyl group of the C-terminal leucine residue (leu309) of the catalytic subunit of protein phosphatase-2A (PPP2CA; MIM 176915) (De Baere et al., 1999 [PubMed 10600115]).[supplied by OMIM, Mar 2008]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 0.87

Clinical Summary— LCMT1

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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?

0.87LOEUF

pLI 0.000

Z-score 2.01

OE 0.53 (0.33–0.87)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.63Z-score

OE missense 0.87 (0.76–0.99)

160 obs / 184.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.53 (0.33–0.87)

0≤0.351.4

Missense OE?0.87 (0.76–0.99)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 11 / 20.9Missense obs/exp: 160 / 184.0Syn Z: -0.06

This gene — mechanism propensity

0.7035th %ile

GOF

0.4974th %ile

LOF

0.2191th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

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