# NM_001985.3(ETFB):c.351G>A (p.Val117=)

https://sugi.bio/variant/etfb-p-val117

## Summary

**ETFB p.Val117= (c.351G>A)** is classified **Likely benign** in ETFB (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-23). Very rare (popmax 0.00167%, amr); Associated with multiple acyl-CoA dehydrogenase deficiency.

**At a glance:** Likely benign · review: Single submitter · rsID rs780821252 · 1 submitter · 1 linked condition · very rare (popmax 0.00167%, amr)

## For patients & families {#patients}

This is a change in the ETFB gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to multiple acyl-CoA dehydrogenase 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) | All ages |
| Prevalence | 1-9 / 1 000 000 (United States) |
| Clinical trials | 4 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | ETFB is a diagnostic-grade gene on 12 Genomics England panels |

**Commonly reported features of Multiple acyl-CoA dehydrogenase deficiency** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Hypotonia — Frequent (79-30%)
- Hypoglycemia — Frequent (79-30%)
- Elevated circulating creatine kinase concentration — Frequent (79-30%)
- Myalgia — Frequent (79-30%)
- Proximal muscle weakness — Frequent (79-30%)
- Exercise-induced muscle fatigue — Frequent (79-30%)
- Phenotypic abnormality — Occasional (29-5%)
- Wide anterior fontanel — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006523/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ETFB](https://sugi.bio/atlas/gene/ETFB/) |
| Protein change (HGVS p.) | p.Val117= |
| Coding change (HGVS c.) | c.351G>A |
| MANE Select transcript | [NM_001985](https://www.ncbi.nlm.nih.gov/nuccore/NM_001985) |
| dbSNP | [rs780821252](https://www.ncbi.nlm.nih.gov/snp/rs780821252/) |
| Variant type | single nucleotide variant |
| Location | chr19:51353156-51353156 (GRCh38) |
| ClinVar | [VCV2768027](https://www.ncbi.nlm.nih.gov/clinvar/variation/2768027/) |

**All HGVS expressions:** `NC_000019.10:g.51353156C>T`, `NC_000019.9:g.51856410C>T`, `NG_007115.1:g.18263G>A`, `NM_001014763.1:c.624G>A`, `NM_001985.3:c.351G>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor gain** (Δ 0.36) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 0.569, GERP 1.39, phastCons 0.908 — weakly conserved position
- CADD: **PHRED 16.96**. 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 deltas (raw): acceptor loss **0.06**, donor loss **0.02**, acceptor gain **0.00**, donor gain **0.36**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.06**, donor loss **0.02**, acceptor gain **0.00**, donor gain **0.36**.
- Population frequency (gnomAD v4.1): grpmax **0.00167%** (amr) · 1/60,026 in the highest group · 1/1,461,800 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}

**ETFB** population constraint: LOEUF 1.1, pLI 2.0928e-05, missense-Z 1.2791. *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):

- **multiple acyl-CoA dehydrogenase deficiency** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 96.19, 96% of residues very-high.

**4 experimental structure(s)** (PDB): [1EFV](https://www.rcsb.org/structure/1EFV), [1T9G](https://www.rcsb.org/structure/1T9G), [2A1T](https://www.rcsb.org/structure/2A1T), [2A1U](https://www.rcsb.org/structure/2A1U) — incl. mutant structure 2A1U.

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

*Describes the biological roles of ETFB (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:** ETFB's established molecular role includes electron transfer activity.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Protein methylation](https://reactome.org/content/detail/R-HSA-8876725) | curated |
| [Respiratory electron transport](https://reactome.org/content/detail/R-HSA-611105) | curated |

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

**Molecular function:** electron transfer activity.

**Biological process:** amino acid catabolic process, respiratory electron transport chain, fatty acid beta-oxidation using acyl-CoA dehydrogenase.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-01-23.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-01-23 |

## Associated conditions {#conditions}

[multiple acyl-CoA dehydrogenase deficiency](https://sugi.bio/atlas/disease/multiple-acyl-coa-dehydrogenase-deficiency/).

**Reported phenotype names (ClinVar):** Multiple acyl-CoA dehydrogenase deficiency, ETHYLMALONIC-ADIPICACIDURIA, GA II, Glutaric aciduria, type 2, Glutaric acidemia type II, GA 2, Glutaric Acidemia type 2.

## Similar variants {#similar}

Related ETFB variant pages (same residue, condition, or type): [ETFB c.375+1G>A](/variant/etfb-c-375-plus-1g-a), [ETFB c.375+1G>T](/variant/etfb-c-375-plus-1g-t), [ETFB p.Arg164Gln](/variant/etfb-p-arg164gln), [ETFB p.Arg21Ter](/variant/etfb-p-arg21ter), [ETFB p.Arg85Ter](/variant/etfb-p-arg85ter), [ETFB p.Cys42Arg](/variant/etfb-p-cys42arg), [ETFB p.Gln136Ter](/variant/etfb-p-gln136ter), [ETFB p.Glu60Ter](/variant/etfb-p-glu60ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 2768027). 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.*