GeneBe

HYCC1

protein-coding

hyccin PI4KA lipid kinase complex subunit 1, the group of PI4KA lipid kinase complex

Gene summary

The protein encoded by this gene may play a part in the beta-catenin/Lef signaling pathway. Expression of this gene is down-regulated by beta-catenin. Defects in this gene are a cause of hypomyelination with congenital cataract (HCC). [provided by RefSeq, Oct 2008]

Previous symbols:
  • FAM126A

MANE transcript

NM_032581.4

Inheritance

AR

ClinVar variants

P:25U:135B:91

Top phenotype

Leukodystrophy, hypomyelinating, 5

gnomAD constraint

pLI —, LoF o/e 0.26

Max pathogenic AF

—

Genomic locus

chr7:22,889,371-23,014,130

External References & Databases

Ensembl (ENSG00000122591)NCBI Gene (84668)OMIM (610531)HGNC:24587GenCCUniProt (Q9BYI3)AlphaFoldClinVar (HYCC1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~124.8 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

leukodystrophy, hypomyelinating, 5DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012514

Submitter: G2P

leukodystrophy, hypomyelinating, 5STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012514

Submitter: PanelApp Australia

leukodystrophy, hypomyelinating, 5DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012514

Submitter: ClinGen

HYCC1 was first reported in association with autosomal hypomyelinating leukodystrophy 5 (OMIM:610532) in 2006 (Zara et al., PMID: 16951682). HYCC1 codes for the Hyccin protein, which is involved in the PI4KA lipid kinase complex and is used for synthesis of phosphatidylinositol 4-phosphate (PI4P). Hyccin is essential for myelin development and growth. Hypomyelinating leukodystrophy 5 is characterized by bilateral congenital cataracts, developmental delay, mild-to-moderate intellectual disability, pyramidal signs and spasticity, cerebellar signs/ataxia, seizures, and scoliosis. MRI findings include hypomyelination and abnormalities of the brainstem pyramidal tract. (PMID: 21911699). Eight variants (2 splice-site, 2 missense, 1 intragenic deletion, 3 frameshift) from 4 publications (PMID: 16951682, 17928815, 23998934, 21911699) have been included in this curation. Segregation data from four families was also scored as genetic evidence in this curation (PMID: 16951682, 17928815). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. Of note, the c.51+1G>A variant and c.414+1G>T variant have been reported in multiple unrelated families as potential founder variants in Mediterranean populations (PMID: 16951682, 21911699, 34192786). The mechanism of pathogenicity for HYCC1 is loss of function. This gene-disease relationship is also supported by experimental evidence. Gazzerro et al. showed that the Hyccin protein is expressed in relevant disease tissues in mice (PMID: 22461884). Zhang et al. demonstrated that Hyccin knockdown Drosophila demonstrated overlapping phenotype with human disease, which was rescued by the expression of the human HYCC1 gene (PMID: 34894559). In summary, there is definitive evidence supporting the relationship between HYCC1 and hypomyelinating leukodystrophy 5 (MONDO: 0012514), also known as HYCC1-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 February 12, 2025 (SOP version 11).

leukodystrophy, hypomyelinating, 5STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012514

Submitter: Labcorp Genetics (formerly Invitae)

leukodystrophy, hypomyelinating, 5SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012514

Submitter: Orphanet

Clinical Genomic Database (CGD)

Leukodystrophy, hypomyelinating, 5AR

Manifestation: Neurologic; Ophthalmologic

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: 16951682Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HYCC1 variants in ClinVar

7 Conditions Cataloged
Hypomyelination and Congenital CataractTotal: 214
Inborn genetic diseasesTotal: 69
not providedTotal: 55
not specifiedTotal: 33
HYCC1-related disorderTotal: 22
FAM126A-related disordersTotal: 2
Tooth agenesis, selective, X-linked, 1Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_032581.4. 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.

EffectPLPVUSLBBSum
synonymous
6
clinvar
76
clinvar
1
clinvar
 83
missense
1
clinvar
1
clinvar
124
clinvar
13
clinvar
1
clinvar
 140
nonsense
1
clinvar
6
clinvar
2
clinvar
 9
start loss
0
frameshift
1
clinvar
7
clinvar
 8
splice donor/acceptor (+/-2bp)
4
clinvar
4
clinvar
3
clinvar
 11
Total718135892251

Highest pathogenic variant AF is 0.000050486164

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 37 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_032581.4RefSeqNP_115970.210MANE Select
ENST00000432176.7EnsemblENSP00000403396.210MANE Select
NM_001363466.2RefSeqNP_001350395.110Standard
NM_001363467.2RefSeqNP_001350396.111Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

  • myelination
  • phosphatidylinositol phosphorylation
  • protein localization to plasma membrane

Molecular Function

  • protein binding

Cellular Component

  • cytosol
  • plasma membrane
  • neuron projection

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000432176
Coding exons
10
Length
72872
Individuals with no LoFs
125724
Homozygous LoFs
0
Heterozygous LoFs
22
Defined
125746
p
0.0000875
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.9812242690.8320.00001313374
Missense (PolyPhen)5995.8130.615781226
Synonymous-1.4111799.21.180.000005181001
Loss of Function3.58727.10.2580.00000136351

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000250.00025rare
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian0.000110.00011rare
Finnish00.0absent
European (Non-Finnish)0.000130.00013rare
South Asian0.0000330.000033rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Component of a complex required to localize phosphatidylinositol 4-kinase (PI4K) to the plasma membrane (PubMed:26571211). The complex acts as a regulator of phosphatidylinositol 4-phosphate (PtdIns(4)P) synthesis (PubMed:26571211). FAM126A plays a key role in oligodendrocytes formation, a cell type with expanded plasma membrane that requires generation of PtdIns(4)P (PubMed:26571211). Its role in oligodendrocytes formation probably explains its importance in myelination of the central and peripheral nervous system (PubMed:26571211, PubMed:16951682). May also have a role in the beta-catenin/Lef signaling pathway (Probable). {ECO:0000269|PubMed:16951682, ECO:0000269|PubMed:26571211, ECO:0000305|PubMed:10910037}.;
Disease
DISEASE: Leukodystrophy, hypomyelinating, 5 (HLD5) [MIM:610532]: A hypomyelinating leukodystrophy associated with congenital cataract. It is clinically characterized by congenital cataract, progressive neurologic impairment, and diffuse myelin deficiency. Affected individuals experience progressive pyramidal and cerebellar dysfunction, muscle weakness and wasting prevailingly in the lower limbs. Mental deficiency ranges from mild to moderate. HLD5 shows clinical variability, but features of hypomyelination combined with increased periventricular white matter water content are consistently observed. {ECO:0000269|PubMed:16951682, ECO:0000269|PubMed:21911699, ECO:0000269|PubMed:23998934, ECO:0000269|PubMed:26571211}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.170

Intolerance Scores

LoFtool
0.507
RVIS EVS
0.26
RVIS percentile EVS
70.52

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
N
Indispensability score
0.486

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
Feedback | API | MCP | Annotate VCF | Sitemap | About | Privacy & Terms
For research and educational, non-commercial use only. Not for clinical or diagnostic use. GeneBe does not provide medical advice. Data use for AI modeling is prohibited: if used, the cost is $0.001 per byte of downloaded uncompressed data.