NUS1

Chr 6ARAD

NUS1 dehydrodolichyl diphosphate synthase subunit

Also known as: C6orf68, CDG1AA, MGC:7199, MRD55, NgBR, TANGO14

NCBI Gene: 116150 ENSG00000153989 UniProt: Q96E22 OMIM: 610463

This protein is essential for dolichol synthesis and protein glycosylation as a subunit of cis-prenyltransferase in the endoplasmic reticulum. Mutations cause congenital disorder of glycosylation type 1aa and intellectual developmental disorder with seizures through loss-of-function mechanisms. The condition follows both autosomal recessive and autosomal dominant inheritance patterns.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a type I single transmembrane domain receptor, which is a subunit of cis-prenyltransferase, and serves as a specific receptor for the neural and cardiovascular regulator Nogo-B. The encoded protein is essential for dolichol synthesis and protein glycosylation. This gene is highly expressed in non-small cell lung carcinomas as well as estrogen receptor-alpha positive breast cancer cells where it promotes epithelial mesenchymal transition. This gene is associated with the poor prognosis of human hepatocellular carcinoma patients. Naturally occurring mutations in this gene cause a congenital disorder of glycosylation and are associated with epilepsy. A knockout of the orthologous gene in mice causes embryonic lethality before day 6.5. Pseudogenes of this gene have been defined on chromosomes 13 and X. [provided by RefSeq, May 2017]

OMIM ResearchGenerating clinical summary…

LOFmechanismAR/ADLOEUF 0.252 OMIM phenotypes

Clinical Summary— NUS1

🧬

Gene-Disease Validity (ClinGen)

progressive myoclonus epilepsy · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡

Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.98). One damaged copy is likely sufficient to cause disease.

📋

ClinVar Variants

90 unique Pathogenic / Likely Pathogenic· 235 VUS of 511 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.25LOEUF

pLI 0.981

Z-score 3.23

OE 0.00 (0.00–0.25)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

0.88Z-score

OE missense 0.80 (0.69–0.93)

126 obs / 156.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.25)

0≤0.351.4

Missense OE?0.80 (0.69–0.93)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 0 / 12.1Missense obs/exp: 126 / 156.9Syn Z: -0.14

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongNUS1-related epilepsy and intellectual disabilityLOFAD

This gene — mechanism propensity

0.3594th %ile

GOF

0.3094th %ile

LOF

0.72top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 1 literature citation · 88% of P/LP variants are LoF · LOEUF 0.25 · ClinGen HI: Sufficient evidence for dosage pathogenicity

Literature Evidence

LOFTwo patients were found by whole-genome sequencing of 197 individuals with developmental epileptic encephalopathy; the third patient was found by clinical exome sequencing from another patient cohort. Studies of the variants and studies of patients cells were not performed, but Hamdan et al. (2017) 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 29100083 ↗

ClinVar Variant Classifications

511 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic57

Likely Pathogenic33

VUS235

Likely Benign157

Benign13

Conflicting11

Pathogenic

Likely Pathogenic

235

VUS

157

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	50	1	6	0	57
Likely Pathogenic	29	3	1	0	33
VUS	2	224	7	2	235
Likely Benign	0	3	53	101	157
Benign	0	1	10	2	13
Conflicting	—				11
Total	81	232	77	105	506

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

View in ClinVar →

30 pathogenic / likely-pathogenic (of 36) ClinVar copy-number / structural variants overlap NUS1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →