# NM_000293.3(PHKB):c.1555dup (p.Thr519fs)

https://sugi.bio/variant/phkb-p-thr519fs

## Summary

**PHKB p.Thr519fs (c.1555dup)** is classified **Pathogenic** in PHKB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-12). Very rare (popmax 0.00167%, amr); Associated with glycogen storage disease IXb.

**At a glance:** Pathogenic · review: Single submitter · 1 submitter · 1 linked condition · very rare (popmax 0.00167%, amr)

## For patients & families {#patients}

This is a change in the PHKB gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to glycogen storage disease IXb.

*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) | Childhood |
| Clinical trials | 2 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | PHKB is a diagnostic-grade gene on 8 Genomics England panels |

**Commonly reported features of Glycogen storage disease due to liver and muscle phosphorylase kinase deficiency** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Hypertriglyceridemia — Very frequent (99-80%)
- Hepatomegaly — Very frequent (99-80%)
- Postnatal growth retardation — Very frequent (99-80%)
- Abnormal enzyme/coenzyme activity — Very frequent (99-80%)
- Hepatic fibrosis — Frequent (79-30%)
- Elevated circulating hepatic transaminase concentration — Frequent (79-30%)
- Hypercholesterolemia — Frequent (79-30%)
- Fasting hypoglycemia — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0016711/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PHKB](https://sugi.bio/atlas/gene/PHKB/) |
| Protein change (HGVS p.) | p.Thr519fs |
| Coding change (HGVS c.) | c.1555dup |
| MANE Select transcript | [NM_000293](https://www.ncbi.nlm.nih.gov/nuccore/NM_000293) |
| Variant type | Duplication |
| Location | chr16:47641636-47641637 (GRCh38) |
| ClinVar | [VCV3622438](https://www.ncbi.nlm.nih.gov/clinvar/variation/3622438/) |

**All HGVS expressions:** `NC_000016.10:g.47641639dup`, `NC_000016.9:g.47675550dup`, `NG_016598.1:g.185341dup`, `NM_000293.3:c.1555dup`, `NM_001031835.3:c.1534dup`, `NM_001363837.1:c.1555dup`

## 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 7.637, GERP 2.73, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.792, pLI 1.2179e-07. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 16 of 31**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication 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 **0.00167%** (amr) · 1/60,022 in the highest group · 1/1,454,248 alleles overall — very rare (popmax 0.00167%, amr).

*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}

**PHKB** population constraint: LOEUF 0.792, pLI 1.2179e-07, missense-Z 0.87257; ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (0–3 scale). *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):

- **glycogen storage disease IXb** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 87.06, 64% of residues very-high.

**6 experimental structure(s)** (PDB): [8JFK](https://www.rcsb.org/structure/8JFK), [8JFL](https://www.rcsb.org/structure/8JFL), [8XYA](https://www.rcsb.org/structure/8XYA), [8Z5P](https://www.rcsb.org/structure/8Z5P), [8Z5Q](https://www.rcsb.org/structure/8Z5Q), [8Z5T](https://www.rcsb.org/structure/8Z5T).

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

*Describes the biological roles of PHKB (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.*


### Pathways affected {#pathways}

PHKB participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Glycogen breakdown (glycogenolysis)](https://reactome.org/content/detail/R-HSA-70221) | electronic |

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

**Biological process:** glycogen catabolic process.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-01-12.

**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 | 2025-01-12 |

## Associated conditions {#conditions}

[glycogen storage disease IXb](https://sugi.bio/atlas/disease/glycogen-storage-disease-ixb/).

**Reported phenotype names (ClinVar):** Glycogen storage disease IXb, GLYCOGENOSIS OF LIVER AND MUSCLE, AUTOSOMAL RECESSIVE, GSD IXb, PHOSPHORYLASE KINASE DEFICIENCY OF LIVER AND MUSCLE, AUTOSOMAL RECESSIVE.

## Similar variants {#similar}

Related PHKB variant pages (same residue, condition, or type): [PHKB p.Thr519=](/variant/phkb-p-thr519), [PHKB p.Asn422fs](/variant/phkb-p-asn422fs), [PHKB c.3144+33_3144+34dup](/variant/phkb-c-3144-plus-33-3144-plus-34dup), [PHKB c.594+1dup](/variant/phkb-c-594-plus-1dup), [PHKB p.Asp318Ter](/variant/phkb-p-asp318ter), [PHKB p.Gln389fs](/variant/phkb-p-gln389fs), [PHKB p.Gln603fs](/variant/phkb-p-gln603fs), [PHKB p.Gln809fs](/variant/phkb-p-gln809fs).

### 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 2026-07-14); 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 3622438). 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.*