# NM_001352514.2(HLCS):c.2361C>T (p.Val787=)

https://sugi.bio/variant/hlcs-p-val787

## Summary

**HLCS p.Val787= (c.2361C>T)** is classified **Benign** in HLCS (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-01). Common (popmax 5.03%, afr) — too common for a highly-penetrant pathogenic allele; Associated with holocarboxylase synthetase deficiency.

**At a glance:** Benign · review: Multiple submitters · rsID rs61732507 · 5 submitters · 1 linked condition · common (popmax 5.03%, afr) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the HLCS gene that is classified as benign — not considered disease-causing, submitted by 5 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.Val787= |
| Coding change (HGVS c.) | c.2361C>T |
| MANE Select transcript | [NM_001352514](https://www.ncbi.nlm.nih.gov/nuccore/NM_001352514) |
| dbSNP | [rs61732507](https://www.ncbi.nlm.nih.gov/snp/rs61732507/) |
| Variant type | single nucleotide variant |
| Location | chr21:36756631-36756631 (GRCh38) |
| ClinVar | [VCV137546](https://www.ncbi.nlm.nih.gov/clinvar/variation/137546/) |

**All HGVS expressions:** `NC_000021.8:g.38128932G>A`, `NC_000021.9:g.36756631G>A`, `NG_016193.2:g.238764C>T`, `NM_000411.8:c.1920C>T`, `NM_001242784.3:c.1920C>T`, `NM_001242785.2:c.1920C>T`, `NM_001352514.2:c.2361C>T`, `NM_001352515.2:c.1920C>T`, `NM_001352516.2:c.1920C>T`, `NM_001352517.1:c.1920C>T`, `NM_001352518.2:c.1920C>T`, `NR_148020.2:n.2445C>T`, `NR_148021.1:n.2602C>T`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 5.03%, afr) — 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 -20, GERP -4.23 — fast-evolving / accelerated position
- CADD: **PHRED 0.002**. 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 **5.03%** (afr) · FAF95 4.9% · FAF99 4.84% · 3,773/74,982 in the highest group · 13,765/1,614,062 alleles overall — common (popmax 5.03%, afr) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Amish (not grpmax-eligible) | 9.12% | 11 |
| African / African-American (grpmax) | 5.03% | 20 |
| South Asian | 1.37% | 73 |
| Ashkenazi Jewish (not grpmax-eligible) | 1.1% | 91 |
| Remaining individuals (not grpmax-eligible) | 0.915% | 109 |
| Admixed American | 0.858% | 117 |
| European (non-Finnish) | 0.606% | 165 |
| Middle Eastern | 0.363% | 276 |
| Finnish (not grpmax-eligible) | 0.0984% | 1,016 |
| East Asian | 0.0312% | 3,206 |

Amish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-01.

**Submitter consensus:** unanimous (5/5 Benign).

**Submission history:** 5 submissions (2014–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2014-03-19 |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Natera, Inc. | Benign | no assertion criteria provided | clinical testing | 2020-09-16 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-01 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Holocarboxylase synthetase deficiency, not specified, not provided, AllHighlyPenetrant, none provided, MULTIPLE CARBOXYLASE DEFICIENCY, EARLY ONSET.

## Similar variants {#similar}

Related HLCS variant pages (same residue, condition, or type): [HLCS p.Val787Ala](/variant/hlcs-p-val787ala), [HLCS c.1620+2T>G](/variant/hlcs-c-1620-plus-2t-g), [HLCS c.1621-2A>G](/variant/hlcs-c-1621-minus-2a-g), [HLCS c.1892+1G>A](/variant/hlcs-c-1892-plus-1g-a), [HLCS c.1960+5G>A](/variant/hlcs-c-1960-plus-5g-a), [HLCS c.2121+1G>A](/variant/hlcs-c-2121-plus-1g-a), [HLCS c.2237-2A>G](/variant/hlcs-c-2237-minus-2a-g), [HLCS c.2450+2T>A](/variant/hlcs-c-2450-plus-2t-a).

### 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 137546). 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.*