ERLIN1

protein-coding

ER lipid raft associated 1, the group of Small nucleolar RNA protein coding host genes

Gene summary

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]

Previous symbols:

C10orf69
SPFH1

MANE transcript

NM_006459.4

Inheritance

ClinVar variants

P:6U:73B:33

Top phenotype

Spastic paraplegia 62, autosomal recessive

gnomAD constraint

pLI —, LoF o/e 0.26

Max pathogenic AF

—

Genomic locus

chr10:100,150,094-100,186,033

External References & Databases

Ensembl (ENSG00000107566)

Transcript & Mutation Effects

hg38 • Region Span ~35.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hereditary spastic paraplegia 62STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014302

Submitter: PanelApp Australia

hereditary spastic paraplegia 62LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014302

Submitter: Ambry Genetics

hereditary spastic paraplegia 62STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014302

Submitter: Labcorp Genetics (formerly Invitae)

hereditary spastic paraplegia 62SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014302

Submitter: Orphanet

hereditary spastic paraplegia 62DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014302

Submitter: ClinGen

*ERLIN1* was first reported in relation to autosomal recessive hereditary spastic paraplegia 62 in 2014 (Novarino G et al. PMID:24482476). Autosomal recessive spastic paraplegia type 62 is a pure or complex form of hereditary spastic paraplegia characterized by spastic paraparesis, most prominent in the lower limbs, and unsteady gait. Onset usually occurs within the first decade of life, although patients have been reported with later onset. Some patients additionally present with increased deep tendon reflexes, amyotrophy, cerebellar ataxia, flexion contractures of the knees and intellectual disability. At least 8 unique variants (2 missense and 6 loss-of-function) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and segregation data. Variants in *ERLIN1* have been reported in individuals with the following disease entities: hereditary spastic paraplegia 62 (MONDO:0014302)(OMIM:615681) and amyotrophic lateral sclerosis (MONDO:0004976). Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found no difference in molecular mechanism, inheritance pattern phenotypic variability. It is recognized that HSP62 can convert to ALS. Therefore, both disease entities were lumped into one, hereditary spastic paraplegia 62, for the purposes of this curation. Variants in this gene have been reported in at least 11 probands in 4 publications (PMIDs: 39367212, 36100157, 24482476, 29453415). Variants in this gene segregated with disease in 11 additional family members across 3 families. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease pair was originally evaluated by the Amyotrophic Lateral Sclerosis Spectrum Disorders GCEP on July 27, 2021. It was reevaluated on April 24, 2025. As a result of this reevaluation, the classification did change. The original curation came to a limited classification as only evidence from ALS was scored. In the reevaluation we decided to lump HSP and ALS. In summary, there is definitive evidence to support the relationship between *ERLIN1* and autosomal recessive hereditary spastic paraplegia 62. This has been repeatedly demonstrated in clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Amyotrophic Lateral Sclerosis Spectrum Disorders GCEP on the meeting date April 24, 2025 (SOP Version 11).

Clinical Genomic Database (CGD)

Spastic paraplegia 62, autosomal recessiveAR

Manifestation: Neurologic

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: 24482476

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ERLIN1 variants in ClinVar

6 Conditions Cataloged

Hereditary spastic paraplegia 62Total: 107

not specifiedTotal: 42

not providedTotal: 18

Hereditary spastic paraplegiaTotal: 8

ERLIN1-related disorderTotal: 2

Juvenile amyotrophic lateral sclerosisTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006459.4. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous				33 clinvar		33
missense	2 clinvar		70 clinvar			72
nonsense		1 clinvar				1
start loss						0
frameshift		2 clinvar				2
splice donor/acceptor (+/-2bp)		1 clinvar	3 clinvar			4
Total	2	4	73	33	0	112

Highest pathogenic variant AF is 0.00000805652

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 16 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006459.4	RefSeq	NP_006450.2	11	MANE Select
ENST00000421367.7	Ensembl	ENSP00000410964.2	11	MANE Select
NM_001100626.2	RefSeq	NP_001094096.1	11	Standard
NM_001347856.2	RefSeq	NP_001334785.1	8	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Disorders of transmembrane transporters
Disease
Defective CFTR causes cystic fibrosis
Transport of small molecules
ABC-family proteins mediated transport

Biological Process

cholesterol metabolic process
ubiquitin-dependent ERAD pathway
SREBP signaling pathway
negative regulation of cholesterol biosynthetic process
negative regulation of fatty acid biosynthetic process

Molecular Function

protein binding
cholesterol binding
ubiquitin protein ligase binding

Cellular Component

endoplasmic reticulum
endoplasmic reticulum membrane
integral component of membrane
protein-containing complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000421367
Coding exons: 11
Length: 38241
Individuals with no LoFs: 125576
Homozygous LoFs: 0
Heterozygous LoFs: 17
Defined: 125593
p: 0.0000677

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.79	115	183	0.628	0.00000912	2274
Missense (PolyPhen)		33	65.643	0.50272		847
Synonymous	0.237	63	65.4	0.963	0.00000338	646
Loss of Function	3.04	5	19.5	0.256	9.06e-7	260

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00026	0.00025	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000062	0.000062	rare
South Asian	0.000066	0.000065	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Component of the ERLIN1/ERLIN2 complex which mediates the endoplasmic reticulum-associated degradation (ERAD) of inositol 1,4,5-trisphosphate receptors (IP3Rs). Involved in regulation of cellular cholesterol homeostasis by regulation the SREBP signaling pathway. Binds cholesterol and may promote ER retention of the SCAP-SREBF complex (PubMed:24217618). {ECO:0000269|PubMed:19240031, ECO:0000269|PubMed:24217618}.;

Recessive Scores

pRec: 0.102

Intolerance Scores

LoFtool: 0.515
RVIS EVS: -0.14
RVIS percentile EVS: 43.29

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.801

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium