# NM_017780.4(CHD7):c.3205C>T (p.Arg1069Ter)

https://sugi.bio/variant/chd7-p-arg1069ter

## Summary

**CHD7 p.Arg1069Ter (c.3205C>T)** is classified **Pathogenic** in CHD7 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2024-12-30). No allele count reported in gnomAD v4.1 (AN 1,612,784); Associated with hypogonadotropic hypogonadism 5 with or without anosmia.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs886040985 · 9 submitters · 2 linked conditions · no allele count reported in gnomAD v4.1 (AN 1,612,784)

## For patients & families {#patients}

This is a change in the CHD7 gene that is considered disease-causing, submitted by 9 submitters, and is linked to hypogonadotropic hypogonadism 5 with or without anosmia.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010773/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CHD7](https://sugi.bio/atlas/gene/CHD7/) |
| Protein change (HGVS p.) | p.Arg1069Ter |
| Coding change (HGVS c.) | c.3205C>T |
| MANE Select transcript | [NM_017780](https://www.ncbi.nlm.nih.gov/nuccore/NM_017780) |
| dbSNP | [rs886040985](https://www.ncbi.nlm.nih.gov/snp/rs886040985/) |
| Variant type | single nucleotide variant |
| Location | chr8:60823843-60823843 (GRCh38) |
| ClinVar | [VCV267423](https://www.ncbi.nlm.nih.gov/clinvar/variation/267423/) |

**All HGVS expressions:** `LRG_176:g.150064C>T`, `LRG_176t1:c.3205C>T`, `NC_000008.10:g.61736402C>T`, `NC_000008.11:g.60823843C>T`, `NG_007009.1:g.150064C>T`, `NM_001316690.1:c.1717-38386C>T`, `NM_017780.4:c.3205C>T`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 7.721, GERP 1.97, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **nonsense (stop-gain)** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene (constraint LOEUF 0.109, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 13 of 38**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 41.0**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.28 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency: **no allele count reported in gnomAD v4.1 (AN 1,612,784)** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**CHD7** population constraint: LOEUF 0.109, pLI 1, missense-Z 3.9606; ClinGen dosage — haploinsufficiency 3, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **CHARGE syndrome** — Definitive (AD)

## Protein context {#protein}

Residue **1069** lies in the helicase atp-binding domain.

**3 experimental structure(s)** (PDB): [2CKC](https://www.rcsb.org/structure/2CKC), [2V0E](https://www.rcsb.org/structure/2V0E), [2V0F](https://www.rcsb.org/structure/2V0F).

## What this gene does {#gene-function}

*Describes the biological roles of CHD7 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*


### Pathways affected {#pathways}

CHD7 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [CHD6, CHD7, CHD8, CHD9 subfamily](https://reactome.org/content/detail/R-HSA-9943962) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Biological process:** skeletal system development, in utero embryonic development, heart morphogenesis, central nervous system development, cranial nerve development, T cell differentiation.

## Clinical significance {#significance}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-12-30.

**Submitter consensus:** conflicting (8 Pathogenic, 1 Likely pathogenic).

**Submission history:** 9 submissions (2016–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genetic Services Laboratory, University of Chicago | Pathogenic | criteria provided, single submitter | clinical testing | 2016-08-22 |
| Sbielas Lab-Department of Human Genetics University of Michigan, University of Michigan Medical School | Pathogenic | no assertion criteria provided | research | 2017-10-27 |
| Fulgent Genetics, Fulgent Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2018-10-31 |
| University of Washington Center for Mendelian Genomics, University of Washington | Likely pathogenic | no assertion criteria provided | research |  |
| Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Pathogenic | criteria provided, single submitter | clinical testing | 2016-09-05 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2024-09-28 |
| 3billion | Pathogenic | criteria provided, single submitter | clinical testing |  |
| Institute of Human Genetics, Heidelberg University | Pathogenic | criteria provided, single submitter | clinical testing | 2024-07-18 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-12-30 |

## Associated conditions {#conditions}

[hypogonadotropic hypogonadism 5 with or without anosmia](https://sugi.bio/atlas/disease/hypogonadotropic-hypogonadism-5-with-or-without-anosmia/), [CHARGE syndrome](https://sugi.bio/atlas/disease/charge-syndrome/).

**Reported phenotype names (ClinVar):** Hypogonadotropic hypogonadism 5 with or without anosmia, CHARGE syndrome, not provided, none provided, HYPOGONADOTROPIC HYPOGONADISM 5 WITH ANOSMIA, HYPOGONADOTROPHIC HYPOGONADISM 5 WITHOUT ANOSMIA, CHD7-Related GnRH Deficiency (Kallmann Syndrome 5), Hittner Hirsch Kreh syndrome, Coloboma, heart anomaly, choanal atresia, retardation, genital and ear anomalies, CHARGE association.

## Similar variants {#similar}

Related CHD7 variant pages (same residue, condition, or type): [CHD7 p.Arg1069Pro](/variant/chd7-p-arg1069pro), [CHD7 p.Arg1069=](/variant/chd7-p-arg1069), [CHD7 p.Arg1069Gln](/variant/chd7-p-arg1069gln), [CHD7 p.Arg1069Gly](/variant/chd7-p-arg1069gly), [CHD7 c.2097-2A>G](/variant/chd7-c-2097-minus-2a-g), [CHD7 c.2238+1G>A](/variant/chd7-c-2238-plus-1g-a), [CHD7 c.2377-1G>A](/variant/chd7-c-2377-minus-1g-a), [CHD7 c.2613+1G>A](/variant/chd7-c-2613-plus-1g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 267423). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*