# NM_001037.5(SCN1B):c.273G>A (p.Val91=)

https://sugi.bio/variant/scn1b-p-val91

## Summary

**SCN1B p.Val91= (c.273G>A)** is classified **Conflicting classifications of pathogenicity** in SCN1B (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-07-30). Ultra-rare (popmax 0.0183%, amr); Associated with Brugada syndrome 5.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs16969926 · 4 submitters · 1 linked condition · ultra-rare (popmax 0.0183%, amr)

## For patients & families {#patients}

This is a change in the SCN1B gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 4 submitters, and is linked to Brugada syndrome 5.

*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, Not applicable |
| Age of onset (of this condition) | Adult, Childhood |
| Prevalence | 1-5 / 10 000 (Europe) |
| Diagnostic panels | SCN1B is a diagnostic-grade gene on 2 Genomics England panels |

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

- Syncope — Frequent (79-30%)
- Cardiac arrest — Frequent (79-30%)
- Right bundle branch block — Frequent (79-30%)
- ST segment elevation — Frequent (79-30%)
- Tachycardia — Occasional (29-5%)
- Ventricular fibrillation — Occasional (29-5%)
- Paroxysmal ventricular tachycardia — Occasional (29-5%)
- Supraventricular tachycardia — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015584/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [SCN1B](https://sugi.bio/atlas/gene/SCN1B/) |
| Protein change (HGVS p.) | p.Val91= |
| Coding change (HGVS c.) | c.273G>A |
| MANE Select transcript | [NM_001037](https://www.ncbi.nlm.nih.gov/nuccore/NM_001037) |
| dbSNP | [rs16969926](https://www.ncbi.nlm.nih.gov/snp/rs16969926/) |
| Variant type | single nucleotide variant |
| Location | chr19:35033564-35033564 (GRCh38) |
| ClinVar | [VCV282734](https://www.ncbi.nlm.nih.gov/clinvar/variation/282734/) |

**All HGVS expressions:** `LRG_420:g.7877G>A`, `LRG_420t1:c.273G>A`, `NC_000019.10:g.35033564G>A`, `NC_000019.9:g.35524468G>A`, `NG_013359.1:g.7877G>A`, `NM_001037.5:c.273G>A`, `NM_001321605.2:c.174G>A`, `NM_199037.5:c.273G>A`

## 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 1.471, GERP -0.571, phastCons 1 — weakly conserved position
- CADD: **PHRED 7.572**. 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 **0.0183%** (amr) · FAF95 0.0102% · FAF99 0.00785% · 11/60,002 in the highest group · 13/1,613,956 alleles overall — ultra-rare (popmax 0.0183%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.0183% | 5,455 |
| South Asian | 0.0011% | 91,078 |
| European (non-Finnish) | 8.47e-05% | 1,179,981 |

*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}

**SCN1B** population constraint: LOEUF 0.71, pLI 0.19763, missense-Z 1.9304; ClinGen dosage — haploinsufficiency 0/3, 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):

- **generalized epilepsy with febrile seizures plus** — Definitive (AD)
- **genetic developmental and epileptic encephalopathy** — Definitive (AR)
- **Brugada syndrome 1** — Disputed (AD)

## Protein context {#protein}

Residue **91** lies in a β-strand; the ig-like c2-type domain.

AlphaFold model confidence (whole protein): pLDDT 87.90, 68% of residues very-high.

**39 experimental structure(s)** (PDB): [21TP](https://www.rcsb.org/structure/21TP), [21TQ](https://www.rcsb.org/structure/21TQ), [25IH](https://www.rcsb.org/structure/25IH), [25II](https://www.rcsb.org/structure/25II), [25IJ](https://www.rcsb.org/structure/25IJ), [6AGF](https://www.rcsb.org/structure/6AGF) — incl. mutant structure 7XVE.

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

*Describes the biological roles of SCN1B (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:** SCN1B's established molecular role includes sodium channel regulator activity. p.Val91= falls in the ig-like c2-type domain.


### Pathways affected {#pathways}

SCN1B participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Phase 0 - rapid depolarisation](https://reactome.org/content/detail/R-HSA-5576892) | curated |
| [Interaction between L1 and Ankyrins](https://reactome.org/content/detail/R-HSA-445095) | electronic |
| [Sensory perception of sweet, bitter, and umami (glutamate) taste](https://reactome.org/content/detail/R-HSA-9717207) | electronic |

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

**Molecular function:** sodium channel regulator activity.

**Biological process:** positive regulation of sodium ion transport, sodium ion transmembrane transport, membrane depolarization, cardiac muscle contraction, regulation of atrial cardiac muscle cell membrane depolarization, cardiac muscle cell action potential involved in contraction.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-07-30.

**Submitter consensus:** conflicting (3 Likely benign, 1 Uncertain significance).

**Submission history:** 4 submissions (2015–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2017-01-23 |
| Eurofins Ntd Llc (ga) | Uncertain significance | criteria provided, single submitter | clinical testing | 2015-08-20 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-07-30 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-09-04 |

## Associated conditions {#conditions}

[Brugada syndrome 5](https://sugi.bio/atlas/disease/brugada-syndrome-5/).

**Reported phenotype names (ClinVar):** Brugada syndrome 5, not specified, not provided, AllHighlyPenetrant, none provided.

## Similar variants {#similar}

Related SCN1B variant pages (same residue, condition, or type): [SCN1B c.449-2A>G](/variant/scn1b-c-449-minus-2a-g), [SCN1B c.449-1G>T](/variant/scn1b-c-449-minus-1g-t), [SCN1B p.Arg85Cys](/variant/scn1b-p-arg85cys), [SCN1B p.Arg85His](/variant/scn1b-p-arg85his), [SCN1B p.Val158Met](/variant/scn1b-p-val158met), [SCN1B c.448+100G>T](/variant/scn1b-c-448-plus-100g-t), [SCN1B c.448+103C>T](/variant/scn1b-c-448-plus-103c-t), [SCN1B c.448+10G>C](/variant/scn1b-c-448-plus-10g-c).

### 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 282734). 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.*