# NM_000126.4(ETFA):c.298_325del (p.Gln100fs)

https://sugi.bio/variant/etfa-p-gln100fs

## Summary

**ETFA p.Gln100fs (c.298_325del)** is classified **Pathogenic/Likely pathogenic** in ETFA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-10-19). Very rare (popmax 0.000593%, nfe); Associated with multiple acyl-CoA dehydrogenase deficiency.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs762158164 · 2 submitters · 1 linked condition · very rare (popmax 0.000593%, nfe)

## For patients & families {#patients}

This is a change in the ETFA gene that is considered likely disease-causing, submitted by 2 submitters, 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 | ETFA 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 | [ETFA](https://sugi.bio/atlas/gene/ETFA/) |
| Protein change (HGVS p.) | p.Gln100fs |
| Coding change (HGVS c.) | c.298_325del |
| MANE Select transcript | [NM_000126](https://www.ncbi.nlm.nih.gov/nuccore/NM_000126) |
| dbSNP | [rs762158164](https://www.ncbi.nlm.nih.gov/snp/rs762158164/) |
| Variant type | Deletion |
| Location | chr15:76292457-76292484 (GRCh38) |
| ClinVar | [VCV2675072](https://www.ncbi.nlm.nih.gov/clinvar/variation/2675072/) |

**All HGVS expressions:** `NC_000015.10:g.76292459_76292486del`, `NC_000015.9:g.76584800_76584827del`, `NG_007077.2:g.23986_24013del`, `NM_000126.4:c.298_325del`, `NM_001127716.2:c.151_178del`

## 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 7.7, GERP 1.56, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.166, pLI 0.0029774. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 4 of 12**, 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 (gnomAD v4.1): grpmax **0.000593%** (nfe) · FAF95 0.000247% · FAF99 0.000159% · 7/1,179,586 in the highest group · 9/1,461,360 alleles overall — very rare (popmax 0.000593%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,482 |
| Finnish (not grpmax-eligible) | 0.00156% | 64,028 |
| European (non-Finnish) (grpmax) | 0.000593% | 168,512 |

Remaining individuals 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}

**ETFA** population constraint: LOEUF 1.166, pLI 0.0029774, missense-Z 0.7966. *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}

Residue **100** lies in the 'domain i' region; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 94.00, 91% 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 ETFA (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:** ETFA's established molecular role includes electron transfer activity. p.Gln100fs falls in the domain i region.


### Pathways affected {#pathways}

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

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

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

**Molecular function:** electron transfer activity, oxidoreductase activity, flavin adenine dinucleotide binding.

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

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2023-10-19.

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

**Submission history:** 2 submissions (2022–2023); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Baylor Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-10-19 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2022-11-29 |

## 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 Acidemia type 2, Glutaric aciduria, type 2, Glutaric acidemia type II, GA 2.

## Similar variants {#similar}

Related ETFA variant pages (same residue, condition, or type): [ETFA p.Gln100His](/variant/etfa-p-gln100his), [ETFA c.658_664+3del](/variant/etfa-c-658-664-plus-3del), [ETFA p.Arg209fs](/variant/etfa-p-arg209fs), [ETFA p.Leu67_Cys68insTer](/variant/etfa-p-leu67-cys68inster), [ETFA p.Lys59fs](/variant/etfa-p-lys59fs), [ETFA c.452-11del](/variant/etfa-c-452-minus-11del), [ETFA c.665-17del](/variant/etfa-c-665-minus-17del), [ETFA c.734-1_744del](/variant/etfa-c-734-minus-1-744del).

### 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 2675072). 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.*