CHD7

Chr 8AD

chromodomain helicase DNA binding protein 7

Also known as: CRG, HH5, IS3, KAL5

NCBI Gene: 55636ENSG00000171316UniProt: Q9P2D1OMIM: 608892

The protein is a chromatin remodeling helicase that functions in the nucleus. Mutations cause CHARGE syndrome and hypogonadotropic hypogonadism with or without anosmia through an autosomal dominant inheritance pattern. The pathogenic mechanism involves loss of function, as the gene is highly intolerant to loss-of-function variants.

GeneReviewsOMIMResearchSummary from RefSeq, OMIM, UniProt, Mechanism
LOFmechanismADLOEUF 0.082 OMIM phenotypes
Clinical Summary— CHD7
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Gene-Disease Validity (ClinGen)
CHARGE syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
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ClinVar Variants
72 unique Pathogenic / Likely Pathogenic· 188 VUS of 400 total submissions
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Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available
Explore recent and relevant literature in Research Assistant →
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GeneReview available — CHD7
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint
0.08LOEUF
pLI 1.000
Z-score 10.48
OE 0.04 (0.02–0.08)
Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint
3.22Z-score
OE missense 0.77 (0.74–0.81)
1254 obs / 1618.5 exp
Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios
LoF OE0.04 (0.02–0.08)
0≤0.351.4
Missense OE0.77 (0.74–0.81)
0≤0.61.4
Synonymous OE1.04
0≤1.21.6
LoF obs/exp: 5 / 137.8Missense obs/exp: 1254 / 1618.5Syn Z: -0.81
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitiveCHD7-related CHARGE syndromeLOFAD
DN
0.2898th %ile
GOF
0.2497th %ile
LOF
0.82top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · 82% of P/LP variants are LoF · LOEUF 0.08
DN1 literature citation

Literature Evidence

DNOverexpression of CHD7 ATPaseK998R mRNA alone produced phenotypes similar to those obtained with low doses of morpholino, indicating that CHD7 ATPaseK998R mRNA acts as a dominant negative.PMID:20130577
LOFDistinct cerebellar foliation anomalies in a CHD7 haploinsufficient mouse model of CHARGE syndrome.PMID:29168327

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

400 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic49
Likely Pathogenic23
VUS188
Likely Benign113
Benign25
Conflicting2
49
Pathogenic
23
Likely Pathogenic
188
VUS
113
Likely Benign
25
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
43
4
2
0
49
Likely Pathogenic
16
5
2
0
23
VUS
2
177
7
2
188
Likely Benign
0
16
34
63
113
Benign
0
15
0
10
25
Conflicting
—2
Total612174575400

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

View in ClinVar →

Protein Context — Lollipop Plot

CHD7 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients