CMTRIC

Genetic Context

HGNC-Approved Gene Symbol

PLEKHG5

Gene Full Name

pleckstrin homology and RhoGEF domain containing G5

Chromosome

1p36.31

Zygosity of Responsible Variant

Homozygous or Compound Heterozygous

Variant Mechanism

Loss of Function (LoF)

Details

Mechanistic basis:
Complete loss

Confidence:
Medium

Prediction:
Published families with CMTRIC point to a biallelic loss-of-function mechanism: PLEKHG5 encodes a guanine nucleotide exchange factor for Rho-family GTPases, and the reported variants, the founder missense p.Arg204Trp together with truncating frameshifts, reduce or abolish that exchange activity. Relatives carrying one variant are unaffected. Other biallelic PLEKHG5 alleles cause a recessive distal spinal muscular atrophy, so the disease alleles at this locus are loss alleles across presentations.

Rationale:
Exchange activity toward Rho-family GTPases is reduced or absent, and a frameshift that removes the catalytic machinery produces the same phenotype as the founder missense allele, which is the signature of a shared floor of lost function. Only a handful of families have been characterized, so the genetics carry more weight here than direct functional work, and the grade reflects that gap.

ClinVar Pathogenic Variants

View PLEKHG5 ClinVar Variants

ClinGen Curation

View PLEKHG5 ClinGen Curation

CMTRIC OMIM Entry

CMTRIC OMIM

PLEKHG5 OMIM Entry

PLEKHG5 OMIM