# NM_000173.7(GP1BA):c.165_168del (p.Ser55fs)

https://sugi.bio/variant/gp1ba-p-ser55fs

## Summary

**GP1BA p.Ser55fs (c.165_168del)** is classified **Likely pathogenic** in GP1BA (ClinVar, Expert panel, 2 submitters; last evaluated 2025-02-11). No gnomAD frequency available for this variant; Associated with Bernard-Soulier syndrome.

**At a glance:** Likely pathogenic · review: Expert panel · rsID rs2151107696 · 2 submitters · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the GP1BA gene that is considered likely disease-causing, submitted by 2 submitters, and is linked to Bernard-Soulier 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) | Autosomal dominant, Autosomal recessive |
| Age of onset (of this condition) | All ages |
| Diagnostic panels | GP1BA is a diagnostic-grade gene on 2 Genomics England panels |

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

- Impaired ristocetin-induced platelet aggregation — Obligate (100%)
- Abnormal bleeding — Very frequent (99-80%)
- Giant platelets — Very frequent (99-80%)
- Decreased platelet glycoprotein Ib-IX-V — Very frequent (99-80%)
- Macrothrombocytopenia — Very frequent (99-80%)
- Menorrhagia — Frequent (79-30%)
- Petechiae — Frequent (79-30%)
- Gastrointestinal hemorrhage — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0002470/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [GP1BA](https://sugi.bio/atlas/gene/GP1BA/) |
| Protein change (HGVS p.) | p.Ser55fs |
| Coding change (HGVS c.) | c.165_168del |
| MANE Select transcript | [NM_000173](https://www.ncbi.nlm.nih.gov/nuccore/NM_000173) |
| dbSNP | [rs2151107696](https://www.ncbi.nlm.nih.gov/snp/rs2151107696/) |
| Variant type | Microsatellite |
| Location | chr17:4932765-4932768 (GRCh38) |
| ClinVar | [VCV2736403](https://www.ncbi.nlm.nih.gov/clinvar/variation/2736403/) |

**All HGVS expressions:** `LRG_480:g.5471TGAG[1]`, `LRG_480t1:c.165_168del`, `NC_000017.10:g.4836060TGAG[1]`, `NC_000017.11:g.4932765TGAG[1]`, `NG_008767.2:g.5471TGAG[1]`, `NM_000173.7:c.165_168del`

## 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 0.093, GERP -2.07, phastCons 0.002 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.289, pLI 0.099846. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (2 of 2)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no microsatellite 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}

**GP1BA** population constraint: LOEUF 1.289, pLI 0.099846, missense-Z 1.4512. *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):

- **Bernard-Soulier syndrome** — Definitive (AR)
- **platelet-type von Willebrand disease** — Definitive (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 64.65, 38% of residues very-high.

**22 experimental structure(s)** (PDB): [1GWB](https://www.rcsb.org/structure/1GWB), [1M0Z](https://www.rcsb.org/structure/1M0Z), [1M10](https://www.rcsb.org/structure/1M10), [1OOK](https://www.rcsb.org/structure/1OOK), [1P8V](https://www.rcsb.org/structure/1P8V), [1P9A](https://www.rcsb.org/structure/1P9A).

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

*Describes the biological roles of GP1BA (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:** GP1BA participates in disease-associated pathways. In Reactome, GP1BA is annotated in disease pathway(s) including **Defective F9 activation**, **Defective binding of VWF variant to GPIb:IX:V**.

**Disease mechanism (Reactome):** GP1BA loss or alteration is curated in [Defective F9 activation](https://reactome.org/content/detail/R-HSA-9673221), [Defective binding of VWF variant to GPIb:IX:V](https://reactome.org/content/detail/R-HSA-9846298), [Enhanced binding of GP1BA variant to VWF multimer:collagen ](https://reactome.org/content/detail/R-HSA-9845620).

### Pathways affected {#pathways}

GP1BA participates in **11 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective F9 activation](https://reactome.org/content/detail/R-HSA-9673221) | curated |
| ⚕ [Defective binding of VWF variant to GPIb:IX:V](https://reactome.org/content/detail/R-HSA-9846298) | curated |
| ⚕ [Enhanced binding of GP1BA variant to VWF multimer:collagen ](https://reactome.org/content/detail/R-HSA-9845620) | curated |
| [Amplification and propagation of coagulation cascade](https://reactome.org/content/detail/R-HSA-9769743) | curated |
| [FXIIa, PKa-dependent activation of coagulation pathway](https://reactome.org/content/detail/R-HSA-9935598) | curated |
| [GP1b-IX-V activation signalling](https://reactome.org/content/detail/R-HSA-430116) | curated |
| [Platelet Adhesion to exposed collagen](https://reactome.org/content/detail/R-HSA-75892) | curated |
| [Platelet Aggregation (Plug Formation)](https://reactome.org/content/detail/R-HSA-76009) | curated |
| [RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function](https://reactome.org/content/detail/R-HSA-8936459) | curated |
| [Regulation of clotting cascade](https://reactome.org/content/detail/R-HSA-9769739) | curated |
| [None](https://reactome.org/content/detail/R-HSA-140837) | other |

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

**Biological process:** cell adhesion, blood coagulation, blood coagulation, intrinsic pathway, positive regulation of platelet activation, fibrinolysis, release of sequestered calcium ion into cytosol.

## Clinical significance {#significance}

**Likely pathogenic** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2025-02-11.

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

**Submission history:** 2 submissions (2023–2025); classifications have differed over time.

**ClinGen expert panel:** Likely Pathogenic — Platelet Disorders VCEP (Bernard-Soulier syndrome). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `PVS1_Strong`, `PM3_Supporting`, `PM2_Supporting`, `PS3_Supporting`, `PP4`.
Inheritance: Autosomal recessive inheritance.

> **Curation rationale (ClinGen, verbatim):** The c.165_168del (p.Ser55ArgfsTer12) variant in GP1BA is a frameshift variant that may cause a premature stop codon that is predicted to escape nonsense mediated decay, however it is  a truncation of a functionally important region (removes the final 598 amino acids) in a gene where loss-of-function is an established disease mechanism (PVS1_Strong). At least one patient (Patient 1 in PMID: 11054083) with this variant had aggregation absent for ristocetin and present for all other agonists, which is highly specific for Bernard-Soulier syndrome (PP4). They also had a history of recurrent epistaxis and spontaneous skin bruises and a low platelet count (84x10^9/l).  This variant has been detected in at least 2 probands with Bernard-Soulier syndrome. One of those individuals was compound heterozygous for this variant and the c.1601_1602del (p.Tyr534CysfsTer?) variant in GP1BA, confirmed in trans by parental testing (PMID: 11054083). This second variant was classified as Pathogenic by the VCEP. (not included here to avoid circularity). The other proband was homozygous for the c.165_168del (p.Ser55ArgfsTer12) variant (PMID: 18791947; PM3_Supporting). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). From PMID: 11054083, flow cytometric analysis was performed for GP Iba on CHO cells transiently transfected with the WT + c.165_168del (p.Ser55ArgfsTer12), which had around 60% WT expression levels above sham. They also tested c.165_168del + c.1601_1602del, which had around 5% WT expression levels above sham. Due to the methods used in this assay (where c.165_168del  was not tested independently), the usual threshold of <25% WT levels to apply PS3_supporting is not the appropriate measure. The 60% expression of WT + c.165_168del is considered sufficient, particularly in light of the c.165_168del + c.1601_1602del, which had around 5% WT expression levels (PS3_supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1_Strong, PP4, PM2_Supporting and PM3_Supporting, PS3_Supporting (VCEP specifications version 1).
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50040 · approved 2025-02-11 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/0a0dff03-9c0b-45d2-86c6-20a97a928d3c).*
*These are ClinGen's applied codes, reported verbatim — Sugi Variant does not re-tally or combine them into its own classification.*

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen | Likely Pathogenic | reviewed by expert panel | curation | 2025-02-11 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-03-03 |

## Associated conditions {#conditions}

[Bernard-Soulier syndrome](https://sugi.bio/atlas/disease/bernard-soulier-syndrome/).

**Reported phenotype names (ClinVar):** Bernard Soulier syndrome, not provided, BLEEDING DISORDER, PLATELET-TYPE, 1, PLATELET GLYCOPROTEIN Ib DEFICIENCY, VON WILLEBRAND FACTOR RECEPTOR DEFICIENCY, Giant platelet syndrome, Hemorrhagiparous thrombocytic dystrophy, Giant platelet disease, GLYCOPROTEIN Ib, PLATELET, DEFICIENCY OF, Platelet Glycoprotein 1b, Deficiency of.

## Similar variants {#similar}

Related GP1BA variant pages (same residue, condition, or type): [GP1BA p.Leu195del](/variant/gp1ba-p-leu195del), [GP1BA p.Leu521fs](/variant/gp1ba-p-leu521fs), [GP1BA p.Val311fs](/variant/gp1ba-p-val311fs), [GP1BA p.Ala318fs](/variant/gp1ba-p-ala318fs), [GP1BA p.Arg358_Trp359insTer](/variant/gp1ba-p-arg358-trp359inster), [GP1BA p.Asn32fs](/variant/gp1ba-p-asn32fs), [GP1BA p.Asn362fs](/variant/gp1ba-p-asn362fs), [GP1BA p.Asp79fs](/variant/gp1ba-p-asp79fs).

### 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 2736403). 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.*