Leukodystrophy, hypomyelinating, 19, transient infantile

Summary

Leukodystrophy, hypomyelinating, 19, transient infantile (MONDO:0032871) is a disease caused by TMEM63A (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: TMEM63A (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 29

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	leukodystrophy, hypomyelinating, 19, transient infantile
Mondo ID	MONDO:0032871
OMIM	618688
DOID	DOID:0070400
UMLS	C5231463
MedGen	1684698
GARD	0025763
Is cancer (heuristic)	no

Also known as: HLD19

Data availability: 29 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › neurodegenerative disease › inherited neurodegenerative disorder › leukodystrophy › leukodystrophy, hypomyelinating, 19, transient infantile

Related subtypes (64): Alexander disease, cerebrotendinous xanthomatosis, polycystic lipomembranous osteodysplasia with sclerosing leukoencephaly, dermatoleukodystrophy, Krabbe disease, Sjogren-Larsson syndrome, Canavan disease, Pelizaeus-Merzbacher spectrum disorder, hereditary spastic paraplegia 2, megalencephalic leukoencephalopathy with subcortical cysts, ribose-5-P isomerase deficiency, hypomyelinating leukodystrophy 5, leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome, hypomyelinating leukodystrophy 6, cystic leukoencephalopathy without megalencephaly, sterol carrier protein 2 deficiency, leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome, hypomyelination with brain stem and spinal cord involvement and leg spasticity, leukoencephalopathy with mild cerebellar ataxia and white matter edema, progressive encephalopathy with leukodystrophy due to DECR deficiency, hypomyelinating leukodystrophy 9, multiple mitochondrial dysfunctions syndrome 4, hypomyelinating leukodystrophy 10, hypomyelinating leukodystrophy 12, hypomyelinating leukodystrophy 13, leukoencephalopathy with bilateral anterior temporal lobe cysts, progressive cavitating leukoencephalopathy, Pelizaeus-Merzbacher-like disease, CADDS, adrenoleukodystrophy, non-progressive predominantly posterior cavitating leukoencephalopathy with peripheral neuropathy, Aicardi-Goutieres syndrome, metachromatic leukodystrophy, peroxisome biogenesis disorder, unknown leukodystrophy, ravine syndrome, leukodystrophy, hypomyelinating, 22, leukodystrophy, hypomyelinating, 23, with ataxia, deafness, liver dysfunction, and dilated cardiomyopathy, neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination, leukodystrophy, hypomyelinating, 18, spastic ataxia 8, autosomal recessive, with hypomyelinating leukodystrophy, leukodystrophy, hypomyelinating, 14, leukodystrophy, hypomyelinating, 20, early-onset calcifying leukoencephalopathy-skeletal dysplasia, c11orf73-related autosomal recessive hypomyelinating leukodystrophy, alkaline ceramidase 3 deficiency, leukodystrophy, hypomyelinating, 15, leukodystrophy, hypomyelinating, 16, leukodystrophy, hypomyelinating, 17, POLR-related leukodystrophy, leukoencephalopathy, diffuse hereditary, with spheroids 1, leukoencephalopathy with vanishing white matter, leukodystrophy, hypomyelinating, 24, leukodystrophy, childhood-onset, remitting, leukodystrophy, hypomyelinating, 25, leukodystrophy, hypomyelinating, 26, with chondrodysplasia, adult-onset progressive leukoencephalopathy-early-onset deafness, leukoencephalopathy, porphyria-related, episodic memory defect leukoencephalopathy, leukodystrophy, hypomyelinating, 28, leukodystrophy, demyelinating, adult-onset, leukodystrophy, adult-onset, autosomal dominant, without amyloid angiopathy, leukoencephalopathy without lacunae, adult-onset, AARS1-related leukoencephalopathy

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

29 retrieved; paginated sample, class counts are floors:

14 uncertain significance, 5 likely pathogenic, 3 benign, 3 pathogenic, 2 likely benign, 1 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1698712	NM_014698.3(TMEM63A):c.1675T>C (p.Tyr559His)	TMEM63A	Pathogenic	no assertion criteria provided
689459	NM_014698.3(TMEM63A):c.503G>A (p.Gly168Glu)	TMEM63A	Pathogenic	criteria provided, multiple submitters, no conflicts
689460	NM_014698.3(TMEM63A):c.1385T>A (p.Ile462Asn)	TMEM63A	Pathogenic	criteria provided, single submitter
689461	NM_014698.3(TMEM63A):c.1699G>A (p.Gly567Ser)	TMEM63A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3068720	NM_014698.3(TMEM63A):c.1658G>A (p.Gly553Asp)	TMEM63A	Likely pathogenic	criteria provided, single submitter
3900600	NM_014698.3(TMEM63A):c.1699G>T (p.Gly567Cys)	TMEM63A	Likely pathogenic	criteria provided, single submitter
3900601	NM_014698.3(TMEM63A):c.583del (p.Leu195fs)	TMEM63A	Likely pathogenic	criteria provided, single submitter
3900602	NM_014698.3(TMEM63A):c.2066G>A (p.Arg689His)	TMEM63A	Likely pathogenic	criteria provided, single submitter
3900603	NM_014698.3(TMEM63A):c.1657G>A (p.Gly553Ser)	TMEM63A	Likely pathogenic	criteria provided, single submitter
2358463	NM_014698.3(TMEM63A):c.2318A>G (p.Gln773Arg)	TMEM63A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1341715	NM_014698.3(TMEM63A):c.598G>A (p.Ala200Thr)	TMEM63A	Uncertain significance	criteria provided, single submitter
1699410	NM_014698.3(TMEM63A):c.2009A>G (p.Gln670Arg)	TMEM63A	Uncertain significance	criteria provided, single submitter
1802267	NM_014698.3(TMEM63A):c.1049C>A (p.Ala350Asp)	TMEM63A	Uncertain significance	criteria provided, single submitter
2575216	NM_014698.3(TMEM63A):c.1657G>T (p.Gly553Cys)	TMEM63A	Uncertain significance	criteria provided, single submitter
2585427	NM_014698.3(TMEM63A):c.887G>A (p.Arg296Gln)	TMEM63A	Uncertain significance	criteria provided, single submitter
3064780	NM_014698.3(TMEM63A):c.2072G>A (p.Gly691Asp)	TMEM63A	Uncertain significance	criteria provided, single submitter
3065543	NM_014698.3(TMEM63A):c.1571+3A>G	TMEM63A	Uncertain significance	criteria provided, single submitter
3067928	NM_014698.3(TMEM63A):c.214AGA[2] (p.Arg74del)	TMEM63A	Uncertain significance	criteria provided, single submitter
3234941	NM_014698.3(TMEM63A):c.2257G>A (p.Val753Met)	TMEM63A	Uncertain significance	criteria provided, single submitter
4076259	NM_014698.3(TMEM63A):c.1009del (p.Glu337fs)	TMEM63A	Uncertain significance	criteria provided, single submitter
4076260	NM_014698.3(TMEM63A):c.3G>A (p.Met1Ile)	TMEM63A	Uncertain significance	criteria provided, single submitter
4080546	NM_014698.3(TMEM63A):c.2413dup (p.Gln805fs)	TMEM63A	Uncertain significance	criteria provided, single submitter
4277873	NM_014698.3(TMEM63A):c.371+2_371+3del	TMEM63A	Uncertain significance	criteria provided, single submitter
4759457	NM_014698.3(TMEM63A):c.1382C>G (p.Pro461Arg)	TMEM63A	Uncertain significance	criteria provided, single submitter
1342228	NM_014698.3(TMEM63A):c.1378-49C>T	TMEM63A	Benign	criteria provided, multiple submitters, no conflicts
1342229	NM_014698.3(TMEM63A):c.1086-48del	TMEM63A	Benign	criteria provided, single submitter
1342230	NM_014698.3(TMEM63A):c.507C>T (p.Asp169=)	TMEM63A	Benign	criteria provided, multiple submitters, no conflicts
4796741	NM_014698.3(TMEM63A):c.1010_1011del (p.Glu337fs)	TMEM63A	Likely benign	criteria provided, single submitter
4819415	NM_014698.3(TMEM63A):c.968A>C (p.Tyr323Ser)	TMEM63A	Likely benign	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 0 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
TMEM63A	Strong	Autosomal dominant	leukodystrophy, hypomyelinating, 19, transient infantile	4

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TMEM63A	HGNC:29118	ENSG00000196187	O94886	Mechanosensitive cation channel TMEM63A	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TMEM63A	Mechanosensitive cation channel TMEM63A	Mechanosensitive cation channel with low conductance and high activation threshold.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
GPCR	1	23.9×	0.042

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TMEM63A	GPCR	yes		CSC1/OSCA1-like_7TM, Nucleotide-bd_a/b_plait_sf, CSC1/OSCA1-like_cyt

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
C1 segment of cervical spinal cord	1
middle frontal gyrus	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TMEM63A	271	ubiquitous	marker	C1 segment of cervical spinal cord, right uterine tube, middle frontal gyrus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TMEM63A	843

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TMEM63A	O94886	6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Neutrophil degranulation	1	23.1×	0.043	TMEM63A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
surfactant secretion	1	8426.0×	2e-04	TMEM63A
lysosome organization	1	306.4×	0.003	TMEM63A

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TMEM63A	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
TMEM63A	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	TMEM63A
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
TMEM63A	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.