# NM_001352514.2(HLCS):c.863del (p.Ser288fs)

https://sugi.bio/variant/hlcs-p-ser288fs

## Summary

**HLCS p.Ser288fs (c.863del)** is classified **Pathogenic/Likely pathogenic** in HLCS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-08). No gnomAD frequency available for this variant; Associated with holocarboxylase synthetase deficiency.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs1015594025 · 2 submitters · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the HLCS gene that is considered likely disease-causing, submitted by 2 submitters, and is linked to holocarboxylase synthetase deficiency.

*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, Infancy, Neonatal |
| Prevalence | 1-9 / 1 000 000 (Europe) |
| Clinical trials | 2 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | HLCS is a diagnostic-grade gene on 10 Genomics England panels |

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

- Irritability — Very frequent (99-80%)
- Keratoconjunctivitis — Very frequent (99-80%)
- Seizure — Very frequent (99-80%)
- Hypotonia — Very frequent (99-80%)
- Growth delay — Very frequent (99-80%)
- Weight loss — Very frequent (99-80%)
- Nausea and vomiting — Very frequent (99-80%)
- Anorexia — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0002721/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [HLCS](https://sugi.bio/atlas/gene/HLCS/) |
| Protein change (HGVS p.) | p.Ser288fs |
| Coding change (HGVS c.) | c.863del |
| MANE Select transcript | [NM_001352514](https://www.ncbi.nlm.nih.gov/nuccore/NM_001352514) |
| dbSNP | [rs1015594025](https://www.ncbi.nlm.nih.gov/snp/rs1015594025/) |
| Variant type | Deletion |
| Location | chr21:36937023-36937023 (GRCh38) |
| ClinVar | [VCV1453907](https://www.ncbi.nlm.nih.gov/clinvar/variation/1453907/) |

**All HGVS expressions:** `NC_000021.8:g.38309323del`, `NC_000021.9:g.36937023del`, `NG_016193.2:g.58372del`, `NM_000411.8:c.422del`, `NM_001242784.3:c.422del`, `NM_001242785.2:c.422del`, `NM_001352514.2:c.863del`, `NM_001352515.2:c.422del`, `NM_001352516.2:c.422del`, `NM_001352517.1:c.422del`, `NM_001352518.2:c.422del`, `NR_148020.2:n.722del`, `NR_148021.1:n.879del`

## 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 -1.436, GERP -4.36 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.883, pLI 1.2982e-11. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 4 of 11**, 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}

**HLCS** population constraint: LOEUF 0.883, pLI 1.2982e-11, missense-Z 1.4537; 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):

- **holocarboxylase synthetase deficiency** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 77.33, 44% of residues very-high.

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

*Describes the biological roles of HLCS (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:** HLCS's established molecular role includes biotin--[biotin carboxyl-carrier protein] ligase activity. In Reactome, HLCS is annotated in disease pathway(s) including **Defective HLCS causes multiple carboxylase deficiency**.

**Disease mechanism (Reactome):** HLCS loss or alteration is curated in [Defective HLCS causes multiple carboxylase deficiency](https://reactome.org/content/detail/R-HSA-3371599).

### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective HLCS causes multiple carboxylase deficiency](https://reactome.org/content/detail/R-HSA-3371599) | curated |
| [Biotin transport and metabolism](https://reactome.org/content/detail/R-HSA-196780) | curated |

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

**Molecular function:** biotin--[biotin carboxyl-carrier protein] ligase activity, biotin binding, enzyme binding.

**Biological process:** post-translational protein modification, response to biotin.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-04-08.

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

**Submission history:** 2 submissions (2023–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-04-08 |
| Baylor Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-03-21 |

## Associated conditions {#conditions}

[holocarboxylase synthetase deficiency](https://sugi.bio/atlas/disease/holocarboxylase-synthetase-deficiency/).

**Reported phenotype names (ClinVar):** Holocarboxylase synthetase deficiency, MULTIPLE CARBOXYLASE DEFICIENCY, EARLY ONSET.

## Similar variants {#similar}

Related HLCS variant pages (same residue, condition, or type): [HLCS c.2114_2121+5del](/variant/hlcs-c-2114-2121-plus-5del), [HLCS p.Arg648fs](/variant/hlcs-p-arg648fs), [HLCS p.Asp544fs](/variant/hlcs-p-asp544fs), [HLCS p.Gln378fs](/variant/hlcs-p-gln378fs), [HLCS p.Gln403_Val404insTer](/variant/hlcs-p-gln403-val404inster), [HLCS p.Gly408fs](/variant/hlcs-p-gly408fs), [HLCS p.Gly519fs](/variant/hlcs-p-gly519fs), [HLCS p.His553fs](/variant/hlcs-p-his553fs).

### 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 1453907). 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.*