LYNX1

Chr 8

Ly6/neurotoxin 1

NCBI Gene: 66004 ENSG00000180155 UniProt: P0DP58 OMIM: 606110

The LYNX1 protein is a membrane-bound modulator of nicotinic acetylcholine receptors that prevents excessive neuronal excitation by enhancing receptor desensitization and regulating receptor trafficking to the cell surface. Mutations in LYNX1 cause autosomal dominant epileptic encephalopathy with onset in infancy, characterized by seizures and developmental delay. The gene shows tolerance to loss-of-function variants, suggesting the pathogenic variants may act through alternative mechanisms.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a GPI-anchored, cell membrane bound member of the Ly6/uPAR (LU) superfamily of proteins containing the unique three-finger LU domain. This protein interacts with nicotinic acetylcholine receptors (nAChRs), and is thought to function as a modulator of nAChR activity to prevent excessive excitation. Alternatively spliced transcript variants have been found for this gene. Read-through transcription between this gene and the neighboring downstream gene (SLURP2) generates naturally-occurring transcripts (LYNX1-SLURP2) that encode a fusion protein comprised of sequence sharing identity with each individual gene product. [provided by RefSeq, Sep 2017]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 1.35

Clinical Summary— LYNX1

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Population Constraint (gnomAD)

Low constraint (pLI 0.03) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

11 VUS of 19 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?

1.35LOEUF

pLI 0.026

Z-score 1.03

OE 0.53 (0.24–1.35)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.97Z-score

OE missense 0.70 (0.56–0.87)

57 obs / 81.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.53 (0.24–1.35)

0≤0.351.4

Missense OE?0.70 (0.56–0.87)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 3 / 5.6Missense obs/exp: 57 / 81.8Syn Z: 0.05

This gene — mechanism propensity

0.73top 25%

GOF

0.5563th %ile

LOF

0.2092th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction 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

19 submitted variants in ClinVar

ClinVar

Classification Summary

VUS11

Benign1

VUS

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	11	0	11
Likely Benign	0	0	0
Benign	0	1	1
Total	11	1	12

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

View in ClinVar →

58 pathogenic / likely-pathogenic (of 72) ClinVar copy-number / structural variants overlap LYNX1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →