# NM_133259.4(LRPPRC):c.3151del

https://sugi.bio/variant/lrpprc-c-3151del

## Summary

**LRPPRC c.3151del** is classified **Likely pathogenic** in LRPPRC (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-11). No gnomAD frequency available for this variant; Associated with congenital lactic acidosis, Saguenay-Lac-Saint-Jean type.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs2466424623 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the LRPPRC gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to congenital lactic acidosis, Saguenay-Lac-Saint-Jean 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 |
| Diagnostic panels | LRPPRC is a diagnostic-grade gene on 11 Genomics England panels |

**Commonly reported features of Congenital lactic acidosis, Saguenay-Lac-Saint-Jean type** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Hypotonia — Very frequent (99-80%)
- Global developmental delay — Very frequent (99-80%)
- Failure to thrive — Very frequent (99-80%)
- Metabolic acidosis — Very frequent (99-80%)
- Increased circulating lactate concentration — Very frequent (99-80%)
- Stroke-like episode — Very frequent (99-80%)
- Increased CSF lactate — Very frequent (99-80%)
- Lactic acidosis — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0008370/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [LRPPRC](https://sugi.bio/atlas/gene/LRPPRC/) |
| Coding change (HGVS c.) | c.3151del |
| MANE Select transcript | [NM_133259](https://www.ncbi.nlm.nih.gov/nuccore/NM_133259) |
| dbSNP | [rs2466424623](https://www.ncbi.nlm.nih.gov/snp/rs2466424623/) |
| Variant type | Deletion |
| Location | chr2:43912556-43912556 (GRCh38) |
| ClinVar | [VCV2676321](https://www.ncbi.nlm.nih.gov/clinvar/variation/2676321/) |

**All HGVS expressions:** `NC_000002.11:g.44139698del`, `NC_000002.12:g.43912559del`, `NG_008247.1:g.88450del`, `NM_133259.4:c.3151del`

## 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 8.698, GERP 0.993, phastCons 1 — highly conserved position (PP3-type support)
- Non-coding constraint (Gnocchi): **Z 0.65**, o/e 0.95 (1 kb window 43,912,000–43,913,000). A higher Z means the window carries less variation than expected. Describes the 1 kb window, not this allele. No ClinGen expert panel references Gnocchi and no ACMG-calibrated threshold exists for it. *Descriptive; no cut-point applied.*
- 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}

**LRPPRC** population constraint: LOEUF 0.808, pLI 2.1588e-11, missense-Z -1.9032; 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):

- **mitochondrial disease** — Definitive (AR)
- **Leigh syndrome** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 77.35, 2% of residues very-high.

**2 experimental structure(s)** (PDB): [8ANY](https://www.rcsb.org/structure/8ANY), [9OLF](https://www.rcsb.org/structure/9OLF).

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

*Describes the biological roles of LRPPRC (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:** LRPPRC's established molecular role includes RNA binding.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Mitochondrial RNA degradation](https://reactome.org/content/detail/R-HSA-9836573) | curated |
| [Mitochondrial mRNA modification](https://reactome.org/content/detail/R-HSA-9937008) | curated |

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

**Molecular function:** RNA binding, mRNA binding, ubiquitin protein ligase binding, beta-tubulin binding.

**Biological process:** mitochondrial mRNA polyadenylation, negative regulation of mitochondrial mRNA catabolic process.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-03-11.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Baylor Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-03-11 |

## Associated conditions {#conditions}

[congenital lactic acidosis, Saguenay-Lac-Saint-Jean type](https://sugi.bio/atlas/disease/congenital-lactic-acidosis-saguenay-lac-saint-jean-type/).

**Reported phenotype names (ClinVar):** Congenital lactic acidosis, Saguenay-Lac-Saint-Jean type, CYTOCHROME c OXIDASE DEFICIENCY, FRENCH CANADIAN TYPE, COX DEFICIENCY, FRENCH CANADIAN TYPE, MITOCHONDRIAL COMPLEX IV DEFICIENCY, NUCLEAR TYPE 5.

## Similar variants {#similar}

Related LRPPRC variant pages (same residue, condition, or type): [LRPPRC c.1730_1735+1del](/variant/lrpprc-c-1730-1735-plus-1del), [LRPPRC c.3710-1del](/variant/lrpprc-c-3710-minus-1del), [LRPPRC p.Ala1051fs](/variant/lrpprc-p-ala1051fs), [LRPPRC p.Ala42fs](/variant/lrpprc-p-ala42fs), [LRPPRC p.Asn1246fs](/variant/lrpprc-p-asn1246fs), [LRPPRC p.Asn454fs](/variant/lrpprc-p-asn454fs), [LRPPRC p.Gln1005fs](/variant/lrpprc-p-gln1005fs), [LRPPRC p.Glu366fs](/variant/lrpprc-p-glu366fs).

### 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 2676321). 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.*