GJC2

protein-coding

gap junction protein gamma 2, the group of Gap junction proteins

Gene summary

This gene encodes a gap junction protein. Gap junction proteins are members of a large family of homologous connexins and comprise 4 transmembrane, 2 extracellular, and 3 cytoplasmic domains. This gene plays a key role in central myelination and is involved in peripheral myelination in humans. Defects in this gene are the cause of autosomal recessive Pelizaeus-Merzbacher-like disease-1. [provided by RefSeq, Jul 2008]

Previous symbols:

GJA12

MANE transcript

NM_020435.4

Inheritance

AD, AR

ClinVar variants

P:87U:234B:92

Top phenotype

Lymphedema malformation 3; Spastic paraplegia 44, autosomal recessive; Leukodystrophy, hypomyelinating, 2

gnomAD constraint

pLI —, LoF o/e 0.54

Max pathogenic AF

—

Genomic locus

chr1:228,149,930-228,159,826

External References & Databases

Ensembl (ENSG00000198835)

Transcript & Mutation Effects

hg38 • Region Span ~9.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

lymphatic malformation 3STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013278

Submitter: Labcorp Genetics (formerly Invitae)

leukodystrophy, hypomyelinating, 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012125

Submitter: ClinGen

GJC2 was first reported in relation to an autosomal recessive hypomyelinating leukodystrophy 2 (HLD2) in 2004 (Uhlenberg et al., PMID: 15192806). Originally, this condition was described as Pelizaeus Merzbacher-like disease given the very similar phenotypic presentation. GJC2 was also reported in association with autosomal recessive spastic paraplegia 44 (SPG44) in 2009 (Orthmann-Murphy et al., PMID 19056803). In this paper, the authors reported a milder phenotype consisting of a later-onset, slowly progressive, complicated spastic paraplegia with hypomyelinating leukoencephalopathy. Additionally, GJC2 was reported in association with autosomal dominant lymphatic malformation 3 (LMPHM3) in 2010 (Ferrekk et al., PMID 20537300). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found that a phenotypic spectrum exists and no difference in molecular mechanism (loss-of-function) or inheritance pattern (autosomal recessive) between HLD2 and SPG44; therefore these two disease entities have been lumped into the HLD2 disease entity (OMIM:608804, MONDO:0012125). However, we did find a difference in molecular mechanism, inheritance pattern, and phenotype between HLD2 and LMPHM3. The latter disease entity has been split to be curated separately. Nine variants (missense, nonsense, and frameshift) that have been reported in seven probands across six publications (PMIDs: 16707726, 31270756, 26354221,15192806, 19056803, 34840390) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease relationship is supported by experimental evidence, including a mouse model (PMID:12805295). In summary, there is definitive evidence supporting the relationship between GJC2 and autosomal recessive hypomyelinating leukodystrophy 2, also known as GLC2-related hypomyelinating leukodystrophy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Leukodystrophy GCEP on January 27, 2025 (SOP Version 11).

leukodystrophy, hypomyelinating, 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012125

Submitter: Ambry Genetics

leukodystrophy, hypomyelinating, 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012125

Submitter: PanelApp Australia

leukodystrophy, hypomyelinating, 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012125

Submitter: G2P

hereditary spastic paraplegia 44STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013179

Submitter: Labcorp Genetics (formerly Invitae)

leukodystrophy, hypomyelinating, 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012125

Submitter: Labcorp Genetics (formerly Invitae)

leukodystrophy, hypomyelinating, 2SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012125

Submitter: Orphanet

lymphatic malformation 3STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013278

Submitter: PanelApp Australia

hereditary spastic paraplegia 44SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013179

Submitter: Orphanet

lymphatic malformation 3MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0013278

Submitter: G2P

Clinical Genomic Database (CGD)

Lymphedema malformation 3; Spastic paraplegia 44, autosomal recessive; Leukodystrophy, hypomyelinating, 2AD/AR

Manifestation: Cardiovascular; Dermatologic; 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

Comments: Individuals with Lymphedema have been described with recurrent skin infections

Refs: 15192806; 16969684; 18094336; 19056803; 20513814; 20537300; 21266381; 21959080; 22610664; 22669416; 23143715; 24374284

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GJC2 variants in ClinVar

16 Conditions Cataloged

Spastic paraplegiaTotal: 241

not providedTotal: 117

Inborn genetic diseasesTotal: 84

Leukodystrophy, hypomyelinating, 2Total: 82

not specifiedTotal: 35

Lymphatic malformation 3Total: 23

GJC2-related disorderTotal: 18

Hereditary spastic paraplegia 44Total: 15

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_020435.4. 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			5 clinvar	80 clinvar	1 clinvar	86
missense	7 clinvar	21 clinvar	223 clinvar	11 clinvar		262
nonsense	10 clinvar	6 clinvar	1 clinvar			17
start loss						0
frameshift	15 clinvar	27 clinvar	5 clinvar			47
splice donor/acceptor (+/-2bp)	1 clinvar					1
Total	33	54	234	91	1	413

Highest pathogenic variant AF is 0.000045279518

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 6 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_020435.4	RefSeq	NP_065168.2	1	MANE Select
ENST00000366714.3	Ensembl	ENSP00000355675.2	1	MANE Select
ENST00000886860.1	Ensembl	ENSP00000556919.1	1	Standard
ENST00000886860.2	Ensembl	ENSP00000556919.1	1	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Calcium Regulation in the Cardiac Cell

Biological Process

regulation of protein phosphorylation
cell-cell signaling
brain development
response to toxic substance
positive regulation of gene expression

Molecular Function

gap junction channel activity involved in cell communication by electrical coupling

Cellular Component

gap junction
connexin complex
integral component of membrane
paranode region of axon
perikaryon

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000366714
Coding exons: 1
Length: 9975
Individuals with no LoFs: 125500
Homozygous LoFs: 0
Heterozygous LoFs: 8
Defined: 125508
p: 0.0000319

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.87	173	258	0.672	0.0000191	2696
Missense (PolyPhen)		82	146.16	0.56101		1389
Synonymous	0.516	121	128	0.942	0.0000105	986
Loss of Function	1.17	4	7.45	0.537	3.22e-7	87

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000037	0.000035	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: One gap junction consists of a cluster of closely packed pairs of transmembrane channels, the connexons, through which materials of low MW diffuse from one cell to a neighboring cell. May play a role in myelination in central and peripheral nervous systems. {ECO:0000269|PubMed:15192806}.;
Disease: DISEASE: Spastic paraplegia 44, autosomal recessive (SPG44) [MIM:613206]: A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. {ECO:0000269|PubMed:19056803}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Lymphedema, hereditary, 1C (LMPH1C) [MIM:613480]: A chronic disabling condition which results in swelling of the extremities due to altered lymphatic flow. Patients with lymphedema suffer from recurrent local infections and physical impairment. {ECO:0000269|PubMed:20537300}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.138

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.374

Gene Damage Prediction

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