HEPACAM
protein-codinghepatic and glial cell adhesion molecule, the group of V-set domain containing|Ig-like cell adhesion molecule family
Gene summary
The protein encoded by this gene is a single-pass type I membrane protein that localizes to the cytoplasmic side of the cell membrane. The encoded protein acts as a homodimer and is involved in cell motility and cell-matrix interactions. The expression of this gene is downregulated or undetectable in many cancer cell lines, so this may be a tumor suppressor gene. [provided by RefSeq, Jul 2011]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~17.2 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0013491
Submitter: ClinGen
Heterozygous variants in HEPACAM, also known as GLIALCAM, have been reported in relation to an autosomal dominant (AD) disorder, megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without intellectual disability (MLC2B), the subject of this curation. Bi-allelic variants in this gene have also been reported in relation to the autosomal recessive (AR) disorder, megalencephalic leukoencephalopathy with subcortical cysts 2A (MLC2A). AD MLC2B is characterized by infantile-onset macrocephaly and mildly delayed motor development related to spontaneously resolving white matter abnormalities. AR MLC2A is characterized by early-onset macrocephaly and delayed onset neurological deterioration including ataxia, spasticity epilepsy and mild cognitive decline. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, there are differences in inheritance pattern and phenotypic variability and therefore, the disorders related to HEPACAM have been split into two disease entities. AR MLC2A has been curated separately. Seven unique variants, including 6 missense and 1 ins/del mutations that have been reported in 22 probands and 3 affected siblings with improving MLC phenotypes in three publications (PMIDs: 21419380, 24202401, 27322623), are included in this curation. Most reported patients inherited their variants from a parent with macrocephaly. The maximum score for genetic evidence (12 pts.) has been reached. In summary, there is definitive evidence to support the relationship between HEPACAM and autosomal dominant megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without intellectual disability. 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 Intellectual Disability and Autism Gene Curation Expert Panel on January 12, 2023 (SOP 9).
Inheritance Pattern: AD
Disease ID:MONDO:0013491
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0013490
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0011391
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0013490
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0013491
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0013490
Submitter: ClinGen
Variants in HEPACAM, also known as GLIALCAM, were first reported by Lopez-Hernandez in 2011 (PMID: 21419380) in relation to the autosomal recessive (AR) condition megalencephalic leukoencephalopathy with subcortical cysts, 2A (MLC2A). Variants in this gene are also implicated in an autosomal dominant (AD) condition, megalencephalic leukoencephalopathy with subcortical cysts 2B (MLC2B). AR MLC2A is characterized by early-onset macrocephaly and delayed-onset neurologic deterioration, including cerebellar ataxia, spasticity, epilepsy, and mild cognitive decline. AD MLC2B is characterized by infantile-onset of macrocephaly and mildly delayed motor development related to spontaneously resolving white matter abnormalities. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, there are differences in inheritance pattern and phenotypic variability and therefore, these two entities have been split and MLC2B has been curated separately. Fourteen variants (10 missense, 2 nonsense, and 2 frameshift) been reported in 13 patients from 11 families (PMIDs: 21419380, 24202401, 27389245, 31372844) are included in this curation. The maximum score for genetic evidence (12 pts.) has been reached. HEPACAM is a direct MLC1-binding partner. The mechanisms of pathogenicity include trafficking defects and impaired interaction between GlialCAM and its protein targets (PMID: 21419380, 31960914). This gene-disease relationship is also supported by expression studies, in vitro/in vivo functional assays and animal models. For example, in cultured cells, coexpression of wild-type MLC1 and HEPACAM missense variants resulted in altered localization of MLC1 and mutated HEPACAM (PMID: 21419380, 25044933). Furthermore, mice harboring homozygous GlialCAM G89S variants showed myelin vacuolization in the cerebellum (PMID: 24647135). In summary, there is definitive evidence to support the relationship between HEPACAM and autosomal recessive megalencephalic leukoencephalopathy with subcortical cysts 2A. 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 Intellectual Disability and Autism Gene Curation Expert Panel on January 12, 2023 (SOP 9).
Inheritance Pattern: AD
Disease ID:MONDO:0011537
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0013491
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0013490
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: 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
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to HEPACAM variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_152722.5. 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 | 4 | 58 | 62 | |||
| missense | 4 | 7 | 151 | 16 | 1 | 179 |
| nonsense | 3 | 2 | 5 | |||
| start loss | 0 | |||||
| frameshift | 4 | 4 | 8 | |||
| splice donor/acceptor (+/-2bp) | 3 | 3 | ||||
| Total | 11 | 16 | 155 | 74 | 1 | 257 |
Highest pathogenic variant AF is 0.000016820439
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_689935.2 | 7 | MANE Select | |
| Ensembl | ENSP00000298251.4 | 7 | MANE Select | |
| RefSeq | NP_001397972.1 | 7 | Standard | |
| RefSeq | NP_001428249.1 | 7 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Biological Process
- cell cycle arrest
- cell adhesion
- cellular protein localization
- regulation of growth
Cellular Component
- cytoplasm
- cell-cell junction
- integral component of membrane
- axon
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000298251
- Coding exons
- 7
- Length
- 17220
- Individuals with no LoFs
- 125719
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 29
- Defined
- 125748
- p
- 0.000115
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.59 | 145 | 210 | 0.691 | 0.0000126 | 2619 |
| Missense (PolyPhen) | 55 | 84.066 | 0.65425 | 936 | ||
| Synonymous | 0.189 | 89 | 91.3 | 0.975 | 0.00000560 | 899 |
| Loss of Function | 3.16 | 2 | 15.4 | 0.130 | 8.99e-7 | 183 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.0013 | 0.0013 | notable |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000035 | 0.000035 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0.00033 | 0.00033 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Involved in regulating cell motility and cell-matrix interactions. May inhibit cell growth through suppression of cell proliferation. {ECO:0000269|PubMed:15885354, ECO:0000269|PubMed:15917256}.;
- Disease
- DISEASE: Leukoencephalopathy, megalencephalic, with subcortical cysts, 2A (MLC2A) [MIM:613925]: A neurodegenerative disorder characterized by infantile-onset macrocephaly and later onset of motor deterioration, with ataxia and spasticity, seizures, and cognitive decline of variable severity. The brain appears swollen on magnetic resonance imaging with white-matter abnormalities and subcortical cysts, in all stages of the disease. {ECO:0000269|PubMed:21419380}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Leukoencephalopathy, megalencephalic, with subcortical cysts, 2B (MLC2B) [MIM:613926]: A neurodegenerative disorder characterized by infantile-onset of macrocephaly and mildly delayed motor development associated with white-matter abnormalities on brain magnetic resonance imaging. The phenotype is milder that MLC2A, with better preserved cerebellar white matter and no subcortical cysts outside the temporal region. On follow-up, patients show normal or almost normal motor function. Some patients have normal intelligence, whereas others have a significant cognitive deficiency. {ECO:0000269|PubMed:21419380}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.115
Intolerance Scores
- LoFtool
- 0.162
- RVIS EVS
- -0.16
- RVIS percentile EVS
- 41.91
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.247
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |