# NM_133642.5(LARGE1):c.96del (p.Ser33fs)

https://sugi.bio/variant/large1-p-ser33fs

## Summary

**LARGE1 p.Ser33fs (c.96del)** is classified **Pathogenic** in LARGE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-28). No gnomAD frequency available for this variant; Associated with muscular dystrophy-dystroglycanopathy type B6.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2520889050 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the LARGE1 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to muscular dystrophy-dystroglycanopathy type B6.

*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.*

|  |  |
| --- | --- |
| Diagnostic panels | LARGE1 is a diagnostic-grade gene on 17 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0024846/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [LARGE1](https://sugi.bio/atlas/gene/LARGE1/) |
| Protein change (HGVS p.) | p.Ser33fs |
| Coding change (HGVS c.) | c.96del |
| MANE Select transcript | [NM_133642](https://www.ncbi.nlm.nih.gov/nuccore/NM_133642) |
| dbSNP | [rs2520889050](https://www.ncbi.nlm.nih.gov/snp/rs2520889050/) |
| Variant type | Deletion |
| Location | chr22:33761381-33761381 (GRCh38) |
| ClinVar | [VCV2747160](https://www.ncbi.nlm.nih.gov/clinvar/variation/2747160/) |

**All HGVS expressions:** `LRG_856:g.164048del`, `LRG_856t1:c.96del`, `LRG_856t2:c.96del`, `NC_000022.10:g.34157370del`, `NC_000022.11:g.33761383del`, `NG_009929.2:g.164048del`, `NM_001362949.2:c.96del`, `NM_001362951.2:c.96del`, `NM_001362953.2:c.96del`, `NM_001378624.1:c.96del`, `NM_001378625.1:c.96del`, `NM_001378626.1:c.96del`, `NM_001378627.1:c.96del`, `NM_001378628.1:c.96del`, `NM_001378629.1:c.96del`, `NM_004737.7:c.96del`, `NM_133642.5:c.96del`

## 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 7.76, GERP 1.82, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.606, pLI 0.00057297. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 of 15**, 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: **no gnomAD frequency available for this variant** — 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}

**LARGE1** population constraint: LOEUF 0.606, pLI 0.00057297, missense-Z 2.7128; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity 0/3. *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):

- **muscular dystrophy-dystroglycanopathy** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 86.15, 70% of residues very-high.

**4 experimental structure(s)** (PDB): [7UI6](https://www.rcsb.org/structure/7UI6), [7UI7](https://www.rcsb.org/structure/7UI7), [7ZVJ](https://www.rcsb.org/structure/7ZVJ), [9E1T](https://www.rcsb.org/structure/9E1T).

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

*Describes the biological roles of LARGE1 (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:** LARGE1's established molecular role includes glucuronosyltransferase activity. In Reactome, LARGE1 is annotated in disease pathway(s) including **Defective LARGE causes MDDGA6 and MDDGB6**.

**Disease mechanism (Reactome):** LARGE1 loss or alteration is curated in [Defective LARGE causes MDDGA6 and MDDGB6](https://reactome.org/content/detail/R-HSA-5083627).

### Pathways affected {#pathways}

LARGE1 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective LARGE causes MDDGA6 and MDDGB6](https://reactome.org/content/detail/R-HSA-5083627) | curated |
| [Matriglycan biosynthesis on DAG1](https://reactome.org/content/detail/R-HSA-9939291) | curated |

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

**Molecular function:** glucuronosyltransferase activity, hexosyltransferase activity, manganese ion binding, xylosyltransferase activity.

**Biological process:** glycoprotein biosynthetic process, protein O-linked glycosylation via mannose.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-06-28.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-06-28 |

## Associated conditions {#conditions}

[muscular dystrophy-dystroglycanopathy type B6](https://sugi.bio/atlas/disease/muscular-dystrophy-dystroglycanopathy-type-b6/).

**Reported phenotype names (ClinVar):** Muscular dystrophy-dystroglycanopathy type B6, MUSCULAR DYSTROPHY, CONGENITAL, LARGE-RELATED, MUSCULAR DYSTROPHY, CONGENITAL, TYPE 1D, MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH IMPAIRED INTELLECTUAL DEVELOPMENT), TYPE B, 6.

## Similar variants {#similar}

Related LARGE1 variant pages (same residue, condition, or type): [LARGE1 p.Ser33=](/variant/large1-p-ser33), [LARGE1 c.788-5_826del](/variant/large1-c-788-minus-5-826del), [LARGE1 p.Glu207fs](/variant/large1-p-glu207fs), [LARGE1 p.Glu63fs](/variant/large1-p-glu63fs), [LARGE1 p.Leu567fs](/variant/large1-p-leu567fs), [LARGE1 p.Leu604fs](/variant/large1-p-leu604fs), [LARGE1 p.Phe162fs](/variant/large1-p-phe162fs), [LARGE1 p.Phe404fs](/variant/large1-p-phe404fs).

### 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 2747160). 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.*