# NM_002296.4(LBR):c.261T>C (p.Pro87=)

https://sugi.bio/variant/lbr-p-pro87

## Summary

**LBR p.Pro87= (c.261T>C)** is classified **Benign** in LBR (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-02-04). Common (popmax 90.6%, eas) — too common for a highly-penetrant pathogenic allele; Associated with Reynolds syndrome.

**At a glance:** Benign · review: Multiple submitters · rsID rs1056608 · 10 submitters · 3 linked conditions · common (popmax 90.6%, eas) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the LBR gene that is classified as benign — not considered disease-causing, submitted by 10 submitters, and is linked to Reynolds syndrome.

*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) | Not applicable |
| Age of onset (of this condition) | Adult |
| Diagnostic panels | LBR is a diagnostic-grade gene on 13 Genomics England panels |

**Commonly reported features of Reynolds syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Pruritus — Very frequent (99-80%)
- Gastroesophageal reflux — Very frequent (99-80%)
- Hepatomegaly — Very frequent (99-80%)
- Myalgia — Very frequent (99-80%)
- Abnormality of the gastric mucosa — Very frequent (99-80%)
- Generalized abnormality of skin — Very frequent (99-80%)
- Fatigue — Very frequent (99-80%)
- Xerostomia — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0004697/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [LBR](https://sugi.bio/atlas/gene/LBR/) |
| Protein change (HGVS p.) | p.Pro87= |
| Coding change (HGVS c.) | c.261T>C |
| MANE Select transcript | [NM_002296](https://www.ncbi.nlm.nih.gov/nuccore/NM_002296) |
| dbSNP | [rs1056608](https://www.ncbi.nlm.nih.gov/snp/rs1056608/) |
| Variant type | single nucleotide variant |
| Location | chr1:225422182-225422182 (GRCh38) |
| ClinVar | [VCV258617](https://www.ncbi.nlm.nih.gov/clinvar/variation/258617/) |

**All HGVS expressions:** `NC_000001.10:g.225609884A>G`, `NC_000001.11:g.225422182A>G`, `NG_008099.1:g.11636T>C`, `NM_002296.4:c.261T>C`, `NM_194442.3:c.261T>C`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 90.6%, eas) — too common for a highly-penetrant pathogenic allele.

- **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 -4.88, GERP -5.31 — fast-evolving / accelerated position
- CADD: **PHRED 1.232**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **90.6%** (eas) · FAF95 89.9% · FAF99 89.6% · 40,665/44,880 in the highest group · 1,237,784/1,613,514 alleles overall — common (popmax 90.6%, eas) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 90.6% | 1 |
| Ashkenazi Jewish (not grpmax-eligible) | 85.9% | 1 |
| Admixed American | 83.7% | 1 |
| Middle Eastern | 82.6% | 1 |
| European (non-Finnish) | 78.8% | 1 |
| Finnish (not grpmax-eligible) | 77.5% | 1 |
| Remaining individuals (not grpmax-eligible) | 77.3% | 1 |
| Amish (not grpmax-eligible) | 72% | 1 |
| South Asian | 65.2% | 2 |
| African / African-American | 38.6% | 3 |

*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}

**LBR** population constraint: LOEUF 0.499, pLI 0.97287, missense-Z 0.94923; 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):

- **Greenberg dysplasia** — Moderate (AR)
- **regressive spondylometaphyseal dysplasia** — Moderate (AR)

## Protein context {#protein}

Residue **87** lies in the 'disordered' region; a UniProt-annotated variant site (in skpha).

AlphaFold model confidence (whole protein): pLDDT 76.89, 46% of residues very-high.

**1 experimental structure(s)** (PDB): [2DIG](https://www.rcsb.org/structure/2DIG).

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

*Describes the biological roles of LBR (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:** LBR's established molecular role includes RNA binding. p.Pro87= falls in the disordered region.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [CDC42 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013148) | curated |
| [Cholesterol biosynthesis via desmosterol (Bloch pathway)](https://reactome.org/content/detail/R-HSA-6807047) | curated |
| [Initiation of Nuclear Envelope (NE) Reformation](https://reactome.org/content/detail/R-HSA-2995383) | curated |
| [RAC1 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013149) | curated |
| [RAC2 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013404) | curated |
| [RAC3 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013423) | curated |
| [RHOA GTPase cycle](https://reactome.org/content/detail/R-HSA-8980692) | curated |
| [RHOC GTPase cycle](https://reactome.org/content/detail/R-HSA-9013106) | curated |
| [RHOD GTPase cycle](https://reactome.org/content/detail/R-HSA-9013405) | curated |
| [RHOG GTPase cycle](https://reactome.org/content/detail/R-HSA-9013408) | curated |
| [Regulation of MECP2 expression and activity](https://reactome.org/content/detail/R-HSA-9022692) | curated |

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

**Molecular function:** RNA binding, Delta14-sterol reductase activity, chromo shadow domain binding, NADPH binding.

**Biological process:** cholesterol biosynthetic process.

## Clinical significance {#significance}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-04.

**Submitter consensus:** unanimous (12/12 Benign).

**Submission history:** 12 submissions (2016–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2018-08-09 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |
| PreventionGenetics, part of Exact Sciences | Benign | criteria provided, single submitter | clinical testing |  |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Benign | criteria provided, single submitter | clinical testing | 2016-03-28 |
| Athena Diagnostics | Benign | criteria provided, single submitter | clinical testing | 2018-05-07 |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-12 |
| Genome-Nilou Lab | Benign | criteria provided, single submitter | clinical testing | 2021-08-19 |
| Blueprint Genetics | Benign | criteria provided, single submitter | clinical testing | 2024-11-26 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2021-04-07 |

## Associated conditions {#conditions}

[Reynolds syndrome](https://sugi.bio/atlas/disease/reynolds-syndrome/), [Pelger-Huet anomaly](https://sugi.bio/atlas/disease/pelger-huet-anomaly/), [Greenberg dysplasia](https://sugi.bio/atlas/disease/greenberg-dysplasia/).

**Reported phenotype names (ClinVar):** Reynolds syndrome, not specified, Greenberg dysplasia, not provided, Pelger-Huët anomaly, none provided, PRIMARY BILIARY CIRRHOSIS, SCLERODERMA, RAYNAUD DISEASE, AND TELANGIECTASIA, Pelger-Huet Anomaly, CHONDRODYSTROPHY, HYDROPIC AND PRENATALLY LETHAL TYPE, HEM SKELETAL DYSPLASIA.

## Similar variants {#similar}

Related LBR variant pages (same residue, condition, or type): [LBR p.Arg512Gln](/variant/lbr-p-arg512gln), [LBR p.Arg583Gln](/variant/lbr-p-arg583gln), [LBR p.Arg586His](/variant/lbr-p-arg586his), [LBR p.Asn547Asp](/variant/lbr-p-asn547asp), [LBR p.Asn547Ser](/variant/lbr-p-asn547ser), [LBR c.*1586G>A](/variant/lbr-c-star-1586g-a), [LBR p.Ala521Ser](/variant/lbr-p-ala521ser), [LBR p.Ala521Thr](/variant/lbr-p-ala521thr).

### 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 258617). 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.*