NDP

Chr XXLDXLR

norrin cystine knot growth factor NDP

Also known as: EVR2, FEVR, ND

NCBI Gene: 4693 ENSG00000124479 UniProt: Q00604 OMIM: 300658

This gene encodes norrin, a secreted protein that activates the canonical Wnt signaling pathway through FZD4 and LRP5 coreceptors and plays a central role in retinal vascularization. Mutations cause Norrie disease and X-linked exudative vitreoretinopathy, both affecting retinal development and vascular formation. The gene shows X-linked inheritance patterns.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a secreted protein with a cystein-knot motif that activates the Wnt/beta-catenin pathway. The protein forms disulfide-linked oligomers in the extracellular matrix. Mutations in this gene result in Norrie disease and X-linked exudative vitreoretinopathy. [provided by RefSeq, Feb 2009]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismXLD/XLRLOEUF 0.882 OMIM phenotypes

Clinical Summary— NDP

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Gene-Disease Validity (ClinGen)

Norrie disease · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.65) — some intolerance to loss-of-function variants.

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ClinVar Variants

68 unique Pathogenic / Likely Pathogenic· 64 VUS of 198 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — NDP

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.88LOEUF

pLI 0.650

Z-score 1.71

OE 0.00 (0.00–0.88)

Moderately constrained

Typical tolerance to LoF variation

Missense Constraint?

0.97Z-score

OE missense 0.62 (0.46–0.83)

31 obs / 50.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.88)

0≤0.351.4

Missense OE?0.62 (0.46–0.83)

0≤0.61.4

Synonymous OE?1.21

0≤1.21.6

LoF obs/exp: 0 / 3.4Missense obs/exp: 31 / 50.4Syn Z: -0.76

ClinVar Variant Classifications

198 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic36

Likely Pathogenic32

VUS64

Likely Benign41

Benign12

Conflicting8

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	19	13	4	0	36
Likely Pathogenic	12	20	0	0	32
VUS	1	52	11	0	64
Likely Benign	0	1	16	24	41
Benign	0	1	9	2	12
Conflicting	—				8
Total	32	87	40	26	193

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

View in ClinVar →

93 pathogenic / likely-pathogenic (of 102) ClinVar copy-number / structural variants overlap NDP — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →