NSDHL

Chr XXLDXLR

NAD(P) dependent 3-beta-hydroxysteroid dehydrogenase NSDHL

Also known as: H105E3, SDR31E1, XAP104

NCBI Gene: 50814 ENSG00000147383 UniProt: Q15738 OMIM: 300275

The protein catalyzes NAD(P)(+)-dependent oxidative decarboxylation of 4-alpha-carboxysterols in post-squalene cholesterol biosynthesis and regulates endocytic trafficking of EGFR. Mutations cause CHILD syndrome and CK syndrome through X-linked dominant inheritance, with the condition typically being lethal in males due to disrupted cholesterol biosynthesis. The gene shows high constraint against loss-of-function variants, suggesting mutations predominantly cause disease through haploinsufficiency.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is localized in the endoplasmic reticulum and is involved in cholesterol biosynthesis. Mutations in this gene are associated with CHILD syndrome, which is a X-linked dominant disorder of lipid metabolism with disturbed cholesterol biosynthesis, and typically lethal in males. Alternatively spliced transcript variants with differing 5' UTR have been found for this gene. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismXLD/XLRLOEUF 0.292 OMIM phenotypes

Clinical Summary— NSDHL

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Gene-Disease Validity (ClinGen)

CK syndrome · XLModerate

Moderate evidence — consider for supplementary testing

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.96). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

16 unique Pathogenic / Likely Pathogenic· 93 VUS of 301 total submissions

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GeneReview available — NSDHL

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.29LOEUF

pLI 0.964

Z-score 2.98

OE 0.00 (0.00–0.29)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

0.87Z-score

OE missense 0.80 (0.69–0.93)

124 obs / 154.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.29)

0≤0.351.4

Missense OE?0.80 (0.69–0.93)

0≤0.61.4

Synonymous OE?1.16

0≤1.21.6

LoF obs/exp: 0 / 10.3Missense obs/exp: 124 / 154.4Syn Z: -1.02

ClinVar Variant Classifications

301 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic9

Likely Pathogenic7

VUS93

Likely Benign70

Benign33

Conflicting19

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	5	3	1	0	9
Likely Pathogenic	2	5	0	0	7
VUS	2	80	10	1	93
Likely Benign	0	17	19	34	70
Benign	0	8	14	11	33
Conflicting	—				19
Total	9	113	44	46	231

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

View in ClinVar →

116 pathogenic / likely-pathogenic (of 143) ClinVar copy-number / structural variants overlap NSDHL — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →