ERLIN1

Chr 10AR

ER lipid raft associated 1

Also known as: C10orf69, Erlin-1, KE04, KEO4, SPFH1, SPG62

NCBI Gene: 10613 ENSG00000107566 UniProt: O75477 OMIM: 611604

ERLIN1 encodes a protein that mediates endoplasmic reticulum-associated degradation of inositol 1,4,5-trisphosphate receptors and regulates cellular cholesterol homeostasis through the SREBP signaling pathway. Mutations cause spastic paraplegia 62, an autosomal recessive disorder affecting the pyramidal motor system. The gene shows moderate tolerance to loss-of-function variants (LOEUF 0.539).

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is part of a protein complex that mediates degradation of inositol 1,4,5-trisphosphate receptors in the endoplasmic reticulum. The encoded protein also binds cholesterol and regulates the SREBP signaling pathway, which promotes cellular cholesterol homeostasis. Defects in this gene have been associated with spastic paraplegia 62. [provided by RefSeq, Dec 2016]

OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.541 OMIM phenotype

Clinical Summary— ERLIN1

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Gene-Disease Validity (ClinGen)

hereditary spastic paraplegia 62 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.26) despite low pLI — interpret in context.

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ClinVar Variants

5 unique Pathogenic / Likely Pathogenic· 75 VUS of 187 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.54LOEUF

pLI 0.178

Z-score 3.04

OE 0.26 (0.13–0.54)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.79Z-score

OE missense 0.63 (0.54–0.73)

115 obs / 183.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.26 (0.13–0.54)

0≤0.351.4

Missense OE?0.63 (0.54–0.73)

0≤0.61.4

Synonymous OE?0.96

0≤1.21.6

LoF obs/exp: 5 / 19.5Missense obs/exp: 115 / 183.1Syn Z: 0.24

This gene — mechanism propensity

0.77top 25%

GOF

0.6345th %ile

LOF

0.2873th %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

187 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3

Likely Pathogenic2

VUS75

Likely Benign67

Benign20

Conflicting5

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	2	0	0	3
Likely Pathogenic	2	0	0	0	2
VUS	3	65	7	0	75
Likely Benign	0	0	38	29	67
Benign	0	1	19	0	20
Conflicting	—				5
Total	6	68	64	29	172

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

View in ClinVar →

13 pathogenic / likely-pathogenic (of 20) ClinVar copy-number / structural variants overlap ERLIN1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →