# NM_000228.3(LAMB3):c.308del (p.Pro103fs)

https://sugi.bio/variant/lamb3-p-pro103fs

## Summary

**LAMB3 p.Pro103fs (c.308del)** is classified **Pathogenic** in LAMB3 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-08-13). Very rare (popmax 0.0044%, sas); Associated with junctional epidermolysis bullosa Herlitz type.

**At a glance:** Pathogenic · review: Single submitter · rsID rs1553279073 · 2 submitters · 1 linked condition · very rare (popmax 0.0044%, sas)

## For patients & families {#patients}

This is a change in the LAMB3 gene that is reported as disease-causing, but on limited review, submitted by 2 submitters, and is linked to junctional epidermolysis bullosa Herlitz type.

*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) | Infancy, Neonatal |
| Prevalence | 1-9 / 1 000 000 (Worldwide) |
| Diagnostic panels | LAMB3 is a diagnostic-grade gene on 3 Genomics England panels |

**Commonly reported features of Severe generalized junctional epidermolysis bullosa** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Fragile skin — Very frequent (99-80%)
- Failure to thrive — Very frequent (99-80%)
- Growth delay — Very frequent (99-80%)
- Recurrent skin infections — Very frequent (99-80%)
- Abnormality of the nail — Very frequent (99-80%)
- Enamel hypoplasia — Very frequent (99-80%)
- Abnormal blistering of the skin — Very frequent (99-80%)
- Abnormal oral mucosa morphology — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0002153/index) · [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.Pro103fs |
| Coding change (HGVS c.) | c.308del |
| MANE Select transcript | [NM_000228](https://www.ncbi.nlm.nih.gov/nuccore/NM_000228) |
| dbSNP | [rs1553279073](https://www.ncbi.nlm.nih.gov/snp/rs1553279073/) |
| Variant type | Deletion |
| Location | chr1:209637972-209637972 (GRCh38) |
| ClinVar | [VCV550189](https://www.ncbi.nlm.nih.gov/clinvar/variation/550189/) |

**All HGVS expressions:** `NC_000001.10:g.209811319del`, `NC_000001.11:g.209637974del`, `NG_007116.1:g.19504del`, `NM_000228.3:c.308del`, `NM_001017402.2:c.308del`, `NM_001127641.1:c.308del`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **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 -0.878, GERP -3.29 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- 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 5 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.
- Population frequency (gnomAD v4.1): grpmax **0.0044%** (sas) · FAF95 0.00143% · FAF99 0.000893% · 4/90,832 in the highest group · 5/1,612,920 alleles overall — very rare (popmax 0.0044%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0044% | 22,708 |
| European (non-Finnish) | 8.48e-05% | 1,179,466 |

*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 **103** lies in the laminin n-terminal domain.

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.Pro103fs falls in the laminin n-terminal domain. 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}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-08-13.

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

**Submission history:** 2 submissions (2017–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Counsyl | Likely pathogenic | no assertion criteria provided | clinical testing | 2017-01-10 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-08-13 |

## Associated conditions {#conditions}

[junctional epidermolysis bullosa Herlitz type](https://sugi.bio/atlas/disease/junctional-epidermolysis-bullosa-herlitz-type/).

**Reported phenotype names (ClinVar):** Junctional epidermolysis bullosa gravis of Herlitz, not provided, none provided, Epidermolysis Bullosa Letalis, EPIDERMOLYSIS BULLOSA JUNCTIONALIS, HERLITZ TYPE, EPIDERMOLYSIS BULLOSA, JUNCTIONAL, HERLITZ-PEARSON TYPE, JEB-HERLITZ TYPE, Herlitz-type junctional epidermolysis bullosa, EPIDERMOLYSIS BULLOSA, JUNCTIONAL 1B, SEVERE.

## Similar variants {#similar}

Related LAMB3 variant pages (same residue, condition, or type): [LAMB3 c.2911_2938del](/variant/lamb3-c-2911-2938del), [LAMB3 p.Ala1055fs](/variant/lamb3-p-ala1055fs), [LAMB3 p.Ala832fs](/variant/lamb3-p-ala832fs), [LAMB3 p.Asn456fs](/variant/lamb3-p-asn456fs), [LAMB3 p.Cys453fs](/variant/lamb3-p-cys453fs), [LAMB3 p.Cys788fs](/variant/lamb3-p-cys788fs), [LAMB3 p.Gly530fs](/variant/lamb3-p-gly530fs), [LAMB3 p.Gly558_Leu559insTer](/variant/lamb3-p-gly558-leu559inster).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 550189). 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.*