# NM_000228.3(LAMB3):c.2376del (p.Arg792fs)

https://sugi.bio/variant/lamb3-p-arg792fs

## Summary

**LAMB3 p.Arg792fs (c.2376del)** is classified **Likely pathogenic** in LAMB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-17). Associated with LAMB3-related disorder.

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

## For patients & families {#patients}

This is a change in the LAMB3 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to LAMB3-related disorder.

*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:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [LAMB3](https://sugi.bio/atlas/gene/LAMB3/) |
| Protein change (HGVS p.) | p.Arg792fs |
| Coding change (HGVS c.) | c.2376del |
| MANE Select transcript | [NM_000228](https://www.ncbi.nlm.nih.gov/nuccore/NM_000228) |
| Variant type | Deletion |
| Location | chr1:209623162-209623162 (GRCh38) |
| ClinVar | [VCV4855544](https://www.ncbi.nlm.nih.gov/clinvar/variation/4855544/) |

**All HGVS expressions:** `NC_000001.10:g.209796508del`, `NC_000001.11:g.209623163del`, `NG_007116.1:g.34314del`, `NM_000228.3:c.2376del`, `NM_001017402.2:c.2376del`, `NM_001127641.1:c.2376del`

## 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 5.44, GERP 1.61, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.829, pLI 6.2848e-23. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 17 of 23**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.

*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}

**LAMB3** population constraint: LOEUF 0.829, pLI 6.2848e-23, missense-Z 0.88919. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **792** lies in the 'domain alpha' region.

AlphaFold model confidence (whole protein): pLDDT 78.55, 23% of residues very-high.

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

*Describes the biological roles of LAMB3 (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:** p.Arg792fs falls in the domain alpha region. In Reactome, LAMB3 is annotated in disease pathway(s) including **Attachment of bacteria to epithelial cells**.

**Disease mechanism (Reactome):** LAMB3 loss or alteration is curated in [Attachment of bacteria to epithelial cells](https://reactome.org/content/detail/R-HSA-9638630).

### Pathways affected {#pathways}

LAMB3 participates in **11 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Attachment of bacteria to epithelial cells](https://reactome.org/content/detail/R-HSA-9638630) | curated |
| [Anchoring fibril formation](https://reactome.org/content/detail/R-HSA-2214320) | curated |
| [Assembly of collagen fibrils and other multimeric structures](https://reactome.org/content/detail/R-HSA-2022090) | curated |
| [Developmental Lineage of Pancreatic Ductal Cells](https://reactome.org/content/detail/R-HSA-9925563) | curated |
| [Developmental Lineage of Pancreatic Endocrine Mid Progenitor Cells](https://reactome.org/content/detail/R-HSA-9981148) | curated |
| [MET activates PTK2 signaling](https://reactome.org/content/detail/R-HSA-8874081) | curated |
| [Type I hemidesmosome assembly](https://reactome.org/content/detail/R-HSA-446107) | curated |
| [Degradation of the extracellular matrix](https://reactome.org/content/detail/R-HSA-1474228) | electronic |
| [Formation of the dystrophin-glycoprotein complex (DGC)](https://reactome.org/content/detail/R-HSA-9913351) | electronic |
| [Laminin interactions](https://reactome.org/content/detail/R-HSA-3000157) | electronic |
| [Non-integrin membrane-ECM interactions](https://reactome.org/content/detail/R-HSA-3000171) | electronic |

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

**Biological process:** endodermal cell differentiation.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-12-17.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| 3billion | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-12-17 |

## Associated conditions {#conditions}

[LAMB3-related disorder](https://sugi.bio/atlas/disease/lamb3-related-disorder/).

**Reported phenotype names (ClinVar):** LAMB3-related disorder, LAMB3-related condition.

## Similar variants {#similar}

Related LAMB3 variant pages (same residue, condition, or type): [LAMB3 c.3383-1G>A](/variant/lamb3-c-3383-minus-1g-a), [LAMB3 c.823-2A>C](/variant/lamb3-c-823-minus-2a-c), [LAMB3 p.Arg42Ter](/variant/lamb3-p-arg42ter), [LAMB3 p.Arg569Ter](/variant/lamb3-p-arg569ter), [LAMB3 p.Arg635Ter](/variant/lamb3-p-arg635ter), [LAMB3 p.Asn345fs](/variant/lamb3-p-asn345fs), [LAMB3 p.Gln117Ter](/variant/lamb3-p-gln117ter), [LAMB3 p.Met1Ile](/variant/lamb3-p-met1ile).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 4855544). 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.*