DHCR7

Chr 11AR

7-dehydrocholesterol reductase

Also known as: SLOS

NCBI Gene: 1717 ENSG00000172893 UniProt: Q9UBM7 OMIM: 602858

DHCR7 encodes an oxidoreductase that catalyzes the final step of cholesterol biosynthesis, converting 7-dehydrocholesterol to cholesterol. Mutations cause Smith-Lemli-Opitz syndrome, an autosomal recessive disorder characterized by intellectual disability, distinctive facial features, syndactyly of the second and third toes, and in severe cases holoprosencephaly, with phenotypic severity ranging from minimal abnormalities with near-normal intelligence to profound developmental delays. The gene shows very low tolerance to loss-of-function variants (pLI near zero), reflecting the critical importance of cholesterol synthesis for normal development.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes an enzyme that removes the C(7-8) double bond in the B ring of sterols and catalyzes the conversion of 7-dehydrocholesterol to cholesterol. This gene is ubiquitously expressed and its transmembrane protein localizes to the endoplasmic reticulum membrane and nuclear outer membrane. Mutations in this gene cause Smith-Lemli-Opitz syndrome (SLOS); a syndrome that is metabolically characterized by reduced serum cholesterol levels and elevated serum 7-dehydrocholesterol levels and phenotypically characterized by cognitive disability, facial dysmorphism, syndactyly of second and third toes, and holoprosencephaly in severe cases to minimal physical abnormalities and near-normal intelligence in mild cases. Alternative splicing results in multiple transcript variants that encode the same protein.[provided by RefSeq, Aug 2009]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Smith-Lemli-Opitz syndromeMIM #270400

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · Smith-Lemli-Opitz syndrome · AR · ClinGen 2023

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

108

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.35

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — DHCR7

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.35LOEUF

pLI 0.000

Z-score 0.31

OE 0.93 (0.65–1.35)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.45Z-score

OE missense 1.07 (0.98–1.18)

322 obs / 300.0 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.93 (0.65–1.35)

0≤0.351.4

Missense OE?1.07 (0.98–1.18)

0≤0.61.4

Synonymous OE?1.21

0≤1.21.6

LoF obs/exp: 20 / 21.5Missense obs/exp: 322 / 300.0Syn Z: -1.88

Background carrier burden — how many people carry a rare variant somewhere in DHCR7?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 37

868 rare PASS variants

Rare truncating (LoF)

1 in 240

142 rare PASS variants

Rare synonymous (reference)

1 in 100

299 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for DHCR7. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 61	1 in 200
South Asian	~43k	1 in 46	1 in 600
Remaining (unassigned)	~30k	1 in 33	1 in 220
European (Finnish)	~27k	1 in 120	1 in 540
Admixed American	~22k	1 in 37	1 in 830
African / African American	~21k	1 in 42	1 in 620
East Asian	~20k	1 in 54	1 in 460
Ashkenazi Jewish	~13k	1 in 290	1 in 800
Middle Eastern	~2,884	1 in 36	1 in 150

Each group is summed over the variants that are rare in that group. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 7 coding exons well covered in gnomAD exomes and genomes.? see exons ↓