DERL1

Chr 8

derlin 1

Also known as: DER-1, DER1, derlin-1

NCBI Gene: 79139 ENSG00000136986 UniProt: Q9BUN8 OMIM: 608813

The encoded protein forms channels in the endoplasmic reticulum membrane that retrotranslocate misfolded proteins from the ER lumen to the cytosol for proteasomal degradation, functioning as a key component of the ER-associated degradation (ERAD) pathway. Biallelic mutations cause infantile-onset epileptic encephalopathy with severe developmental delay, microcephaly, and visual impairment, following an autosomal recessive inheritance pattern. The gene shows low constraint against loss-of-function variants, consistent with the recessive disease mechanism.

OMIM ResearchSummary from RefSeq, UniProt

The protein encoded by this gene is a member of the derlin family. Members of this family participate in the ER-associated degradation response and retrotranslocate misfolded or unfolded proteins from the ER lumen to the cytosol for proteasomal degradation. This protein recognizes substrate in the ER and works in a complex to retrotranslocate it across the ER membrane into the cytosol. This protein may select cystic fibrosis transmembrane conductance regulator protein (CFTR) for degradation as well as unfolded proteins in Alzheimer's disease. Alternative splicing results in multiple transcript variants that encode different protein isoforms. [provided by RefSeq, Aug 2012]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.84

Clinical Summary— DERL1

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

32 VUS of 52 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.84LOEUF

pLI 0.000

Z-score 2.07

OE 0.48 (0.29–0.84)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.12Z-score

OE missense 0.74 (0.63–0.86)

104 obs / 141.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.48 (0.29–0.84)

0≤0.351.4

Missense OE?0.74 (0.63–0.86)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 9 / 18.7Missense obs/exp: 104 / 141.5Syn Z: 0.11

This gene — mechanism propensity

0.88top 5%

GOF

0.75top 25%

LOF

0.1895th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

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.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

52 submitted variants in ClinVar

ClinVar

Classification Summary

VUS32

VUS

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	32	32
Likely Benign	0	0
Benign	0	0
Total	32	32

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

View in ClinVar →

48 pathogenic / likely-pathogenic (of 49) ClinVar copy-number / structural variants overlap DERL1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →