# NM_000071.3(CBS):c.119_120dup (p.Pro41fs)

https://sugi.bio/variant/cbs-p-pro41fs

## Summary

**CBS p.Pro41fs (c.119_120dup)** is classified **Likely pathogenic** in CBS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-09). Associated with classic homocystinuria.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 1 linked condition

## For patients & families {#patients}

This is a change in the CBS gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to classic homocystinuria.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Adolescent, Adult, Childhood |
| Prevalence | 1-9 / 1 000 000 (Worldwide) |
| Clinical trials | 3 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | CBS is a diagnostic-grade gene on 11 Genomics England panels |

**Commonly reported features of Homocystinuria due to cystathionine beta-synthase deficiency** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Dental crowding — Very frequent (99-80%)
- Osteoporosis — Very frequent (99-80%)
- Ectopia lentis — Very frequent (99-80%)
- Arachnodactyly — Very frequent (99-80%)
- Intellectual disability — Very frequent (99-80%)
- Disproportionate tall stature — Very frequent (99-80%)
- Hyperhomocystinemia — Very frequent (99-80%)
- Recurrent fractures — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006667/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CBS](https://sugi.bio/atlas/gene/CBS/) |
| Protein change (HGVS p.) | p.Pro41fs |
| Coding change (HGVS c.) | c.119_120dup |
| MANE Select transcript | [NM_000071](https://www.ncbi.nlm.nih.gov/nuccore/NM_000071) |
| Variant type | Duplication |
| Location | chr21:43072073-43072074 (GRCh38) |
| ClinVar | [VCV4816484](https://www.ncbi.nlm.nih.gov/clinvar/variation/4816484/) |

**All HGVS expressions:** `LRG_777:g.8856_8857dup`, `LRG_777t1:c.118_119dup`, `NC_000021.8:g.44492185_44492186dup`, `NC_000021.9:g.43072075_43072076dup`, `NG_008938.1:g.8856_8857dup`, `NM_000071.2:c.119_120dup`, `NM_000071.3:c.119_120dup`, `NM_001178008.3:c.119_120dup`, `NM_001178009.3:c.119_120dup`, `NM_001320298.2:c.119_120dup`

## 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 4.111, GERP 1.51, phastCons 0.836 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 3 of 17**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Repeat context: **segmental_duplication** (chr21:6427258). Short reads may not map uniquely here, so both the call and its population frequency are less reliable. *A qualifier on how reliably this variant can be called and counted — not a pathogenicity signal.*

*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}


Curated gene–disease validity (ClinGen):

- **classic homocystinuria** — Definitive (AR)

## Protein context {#protein}

Residue **41** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 90.15, 75% of residues very-high.

**28 experimental structure(s)** (PDB): [1JBQ](https://www.rcsb.org/structure/1JBQ), [1M54](https://www.rcsb.org/structure/1M54), [4COO](https://www.rcsb.org/structure/4COO), [4L0D](https://www.rcsb.org/structure/4L0D), [4L27](https://www.rcsb.org/structure/4L27), [4L28](https://www.rcsb.org/structure/4L28) — incl. mutant structure 4L27.

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

*Describes the biological roles of CBS (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.*

**How this variant is thought to act:** CBS's established molecular role includes cystathionine beta-synthase activity. p.Pro41fs falls in the disordered region.


### Pathways affected {#pathways}

CBS participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Cysteine formation from homocysteine](https://reactome.org/content/detail/R-HSA-1614603) | curated |
| [Metabolism of ingested SeMet, Sec, MeSec into H2Se](https://reactome.org/content/detail/R-HSA-2408508) | electronic |

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

**Molecular function:** cystathionine beta-synthase activity, oxygen binding, enzyme binding, heme binding, pyridoxal phosphate binding, ubiquitin protein ligase binding.

**Biological process:** L-serine metabolic process, L-serine catabolic process, L-cysteine biosynthetic process, L-cysteine catabolic process, DNA protection, L-homocysteine catabolic process.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-06-09.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Natera, Inc. | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-06-09 |

## Associated conditions {#conditions}

[classic homocystinuria](https://sugi.bio/atlas/disease/classic-homocystinuria/).

**Reported phenotype names (ClinVar):** Classic homocystinuria, HOMOCYSTINURIA WITH OR WITHOUT RESPONSE TO PYRIDOXINE, Homocystinuria due to CBS deficiency, Cystathionine beta-synthase deficiency, CBS deficiency, Homocystinuria due to Cystathionine Beta-Synthase Deficiency.

## Similar variants {#similar}

Related CBS variant pages (same residue, condition, or type): [CBS p.Pro41Leu](/variant/cbs-p-pro41leu), [CBS p.Ala71fs](/variant/cbs-p-ala71fs), [CBS p.Gln7fs](/variant/cbs-p-gln7fs), [CBS p.Met126fs](/variant/cbs-p-met126fs), [CBS c.452-153_624dup](/variant/cbs-c-452-minus-153-624dup), [CBS p.Ala186fs](/variant/cbs-p-ala186fs), [CBS p.Glu283fs](/variant/cbs-p-glu283fs), [CBS p.His203fs](/variant/cbs-p-his203fs).

### 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 2026-10-14); 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 4816484). 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.*