PLEKHG5

protein-coding

pleckstrin homology and RhoGEF domain containing G5, the group of Pleckstrin homology domain containing|Dbl family Rho GEFs

Gene summary

This gene encodes a protein that activates the nuclear factor kappa B (NFKB1) signaling pathway. Mutations in this gene are associated with autosomal recessive distal spinal muscular atrophy. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2012]

MANE transcript

NM_020631.6

Inheritance

ClinVar variants

P:96U:520B:425

Top phenotype

Charcot-Marie-Tooth disease, recessive intermediate C; Neuronopathy, distal hereditary motor, autosomal recessive 4

gnomAD constraint

pLI —, LoF o/e 0.38

Max pathogenic AF

—

Genomic locus

chr1:6,467,122-6,520,074

External References & Databases

Ensembl (ENSG00000171680)

Transcript & Mutation Effects

hg38 • Region Span ~53.0 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neuromuscular diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019056

Submitter: ClinGen

PLEKHG5 was first reported in relation to autosomal recessive distal spinal muscular atrophy 4 in 2007 (Maystadt et al., PMID:17564964). Spinal muscular atrophy, distal, autosomal recessive, 4 (OMIM:611067) and Charcot-Marie-Tooth disease, recessive intermediate C (OMIM:615376) have been lumped into one disease entity, neuromuscular disease (MONDO:0019056), for this curation. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, no difference in inheritance pattern, and overlapping phenotypes. Five variants (missense, frameshift, and nonsense) that have been reported in four probands in three publications (PMIDs:17564964, 23777631, 23844677) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) was nearly reached. Mutations cluster in the Pleckstrin-Homology Domain and Rho-Guanine Exchange Factor Domain. The mechanism of pathogenicity is reported to be loss of function and involves aggregate formation. Case-level functional data supporting pathogenicity include luciferase reporter assays showing significant reduction of nuclear factor-κB (NFkB) signaling activation and immunofluorescence assays displaying formation of aggregates in cells expressing mutant PLEKHG5 (PMIDs:17564964, 23844677). This gene-disease relationship is also supported by a PLEKHG5 knockout mouse models (PMID:29084947). PLEKHG5 gene inactivation in mice resulted in a late-onset motoneuron disease, characterized by degeneration of axon terminals. An experiment treating PLEKHG5 deficient murine motoneurons with constitutively activated Rab26 rescued NFkB activation levels, but was not included in the score of this curation (PMID:29084947). Rab26 is not a direct gene product of PLEKHG5 and therefore not congruent with ClinGen scoring guidelines for rescue models. In summary, there is definitive evidence supporting the relationship between PLEKHG5 and autosomal recessive neuromuscular disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over. This classification was approved by the ClinGen Charcot-Marie-Tooth Disease GCEP on April 25, 2023 (SOP Version 9).

neuronopathy, distal hereditary motor, autosomal recessive 4LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0012608

Submitter: Ambry Genetics

Charcot-Marie-Tooth disease recessive intermediate CMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014154

Submitter: Ambry Genetics

hereditary peripheral neuropathySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0020127

Submitter: PanelApp Australia

neuronopathy, distal hereditary motor, autosomal recessive 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012608

Submitter: Labcorp Genetics (formerly Invitae)

Charcot-Marie-Tooth disease recessive intermediate CSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014154

Submitter: Labcorp Genetics (formerly Invitae)

Charcot-Marie-Tooth disease recessive intermediate CSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014154

Submitter: Orphanet

neuronopathy, distal hereditary motor, autosomal recessive 4SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012608

Submitter: Orphanet

Clinical Genomic Database (CGD)

Charcot-Marie-Tooth disease, recessive intermediate C; Neuronopathy, distal hereditary motor, autosomal recessive 4AR

Manifestation: Musculoskeletal; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 16728649; 17564964; 23777631; 23844677

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PLEKHG5 variants in ClinVar

15 Conditions Cataloged

Neuronopathy, distal hereditary motor, autosomal recessive 4Total: 1213

Charcot-Marie-Tooth disease recessive intermediate CTotal: 1207

Inborn genetic diseasesTotal: 326

not providedTotal: 293

not specifiedTotal: 137

PLEKHG5-related disorderTotal: 109

Juvenile amyotrophic lateral sclerosisTotal: 2

Hereditary neuropathy or pain disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_020631.6. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			6 clinvar	388 clinvar	5 clinvar	399
missense		4 clinvar	507 clinvar	26 clinvar	4 clinvar	541
nonsense	15 clinvar	10 clinvar	1 clinvar			26
start loss	1 clinvar		2 clinvar			3
frameshift	35 clinvar	12 clinvar	2 clinvar		2 clinvar	51
splice donor/acceptor (+/-2bp)	1 clinvar	18 clinvar	2 clinvar			21
Total	52	44	520	414	11	1041

Highest pathogenic variant AF is 0.00046983626

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 57 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_020631.6	RefSeq	NP_065682.2	20	MANE Select
ENST00000377728.8	Ensembl	ENSP00000366957.3	20	MANE Select
NM_001042663.3	RefSeq	NP_001036128.2	21	Standard
NM_001042664.2	RefSeq	NP_001036129.1	20	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
plekhg5b	Danio rerio	Structure: dorsal longitudinal anastomotic vessel Quality: aplastic abnormal

Gene / Model

Organism

Observed Phenotype

plekhg5b

Danio rerio

Structure: dorsal longitudinal anastomotic vessel

Quality: aplastic

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Pathways in cancer - Homo sapiens (human)
Signaling by GPCR
Signal Transduction
Rho GTPase cycle
Signaling by Rho GTPases

Biological Process

G protein-coupled receptor signaling pathway
regulation of Rho protein signal transduction
endothelial cell chemotaxis
positive regulation of apoptotic process
positive regulation of I-kappaB kinase/NF-kappaB signaling

Molecular Function

guanyl-nucleotide exchange factor activity
Rho guanyl-nucleotide exchange factor activity

Cellular Component

cytoplasm
cytosol
plasma membrane
cell-cell junction
lamellipodium

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000537245
Coding exons: 22
Length: 53970
Individuals with no LoFs: 124246
Homozygous LoFs: 49
Heterozygous LoFs: 1452
Defined: 125747
p: 0.00599

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.49	552	660	0.837	0.0000450	6913
Missense (PolyPhen)		226	292.23	0.77337		3105
Synonymous	-0.181	288	284	1.01	0.0000195	2197
Loss of Function	3.94	18	47.2	0.381	0.00000249	546

Population LoF Frequency

Population	CAF	p-value	Status
African	0.091	0.082	notable
Latino/Admixed American	0.0038	0.0034	notable
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00016	0.00016	rare
Finnish	0.000047	0.000046	rare
European (Non-Finnish)	0.00070	0.00069	rare
South Asian	0.00037	0.00036	rare
Other	0.0026	0.0023	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Guanine nucleotide exchange factor that activates RHOA and maybe the NF-kappa-B signaling pathway. Involved in the control of neuronal cell differentiation. Plays a role in angiogenesis through regulation of endothelial cells chemotaxis. {ECO:0000269|PubMed:11704860, ECO:0000269|PubMed:12761501}.;
Disease: DISEASE: Charcot-Marie-Tooth disease, recessive, intermediate type, C (CMTRIC) [MIM:615376]: A form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Recessive intermediate forms of Charcot-Marie-Tooth disease are characterized by clinical and pathologic features intermediate between demyelinating and axonal peripheral neuropathies, and motor median nerve conduction velocities ranging from 25 to 45 m/sec. {ECO:0000269|PubMed:23777631, ECO:0000269|PubMed:23844677}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.506

Intolerance Scores

LoFtool: 0.803
RVIS EVS: 1.15
RVIS percentile EVS: 92.39

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.375

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	High
Cancer	Medium	Medium	Medium