HEPACAM

Chr 11ARAD

hepatic and glial cell adhesion molecule

Also known as: GlialCAM, MLC2A, MLC2B

NCBI Gene: 220296 ENSG00000165478 UniProt: Q14CZ8 OMIM: 611642

HEPACAM encodes a membrane protein that regulates cell motility and cell-matrix interactions, and in glia it targets the chloride channel CLCN2 to astrocytic processes where it regulates chloride flux involved in neuronal excitability. Mutations cause megalencephalic leukoencephalopathy with subcortical cysts, which can present as either a severe progressive form (type 2A) or a milder remitting form (type 2B) that may occur with or without intellectual disability. The gene shows high constraint against loss-of-function variants and follows both autosomal recessive and autosomal dominant inheritance patterns.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismAR/ADLOEUF 0.412 OMIM phenotypes

Clinical Summary— HEPACAM

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Gene-Disease Validity (ClinGen)

megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without intellectual disability · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.87) — some intolerance to loss-of-function variants.

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ClinVar Variants

23 unique Pathogenic / Likely Pathogenic· 178 VUS of 326 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — HEPACAM

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.41LOEUF

pLI 0.868

Z-score 3.16

OE 0.13 (0.05–0.41)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.59Z-score

OE missense 0.69 (0.60–0.79)

145 obs / 209.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.13 (0.05–0.41)

0≤0.351.4

Missense OE?0.69 (0.60–0.79)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 2 / 15.4Missense obs/exp: 145 / 209.9Syn Z: 0.19

This gene — mechanism propensity

0.5869th %ile

GOF

0.6931th %ile

LOF

0.55top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF1 literature citation · 52% of P/LP variants are LoF · LOEUF 0.41

GOFprediction 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.

Literature Evidence

LOFWe therefore suggest that haploinsufficiency of HEPACAM, a gene previously associated with the features of MLC2 and located on the overlapping deletion region between the two patients, might be related to the observed white matter abnormalities.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 26193381 ↗

ClinVar Variant Classifications

326 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic11

Likely Pathogenic12

VUS178

Likely Benign79

Benign22

Conflicting21

Pathogenic

Likely Pathogenic

178

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	7	4	0	0	11
Likely Pathogenic	5	7	0	0	12
VUS	0	136	40	2	178
Likely Benign	0	7	33	39	79
Benign	0	4	14	4	22
Conflicting	—				21
Total	12	158	87	45	323

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

61 pathogenic / likely-pathogenic (of 67) ClinVar copy-number / structural variants overlap HEPACAM — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →