# NM_000126.4(ETFA):c.806TAG[1] (p.Val270del)

https://sugi.bio/variant/etfa-p-val270del

## Summary

**ETFA p.Val270del (c.806TAG[1])** is classified **Conflicting classifications of pathogenicity** in ETFA (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2025-07-28). Very rare (popmax 0.00562%, nfe); Associated with Glutaric acidemia type 2A.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs779140971 · 9 submitters · 3 linked conditions · very rare (popmax 0.00562%, nfe)

## For patients & families {#patients}

This is a change in the ETFA gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 9 submitters, and is linked to Glutaric acidemia type 2A.

*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.*

**Support & next steps:** [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.Val270del |
| Coding change (HGVS c.) | c.806TAG[1] |
| MANE Select transcript | [NM_000126](https://www.ncbi.nlm.nih.gov/nuccore/NM_000126) |
| dbSNP | [rs779140971](https://www.ncbi.nlm.nih.gov/snp/rs779140971/) |
| Variant type | Microsatellite |
| Location | chr15:76274417-76274419 (GRCh38) |
| ClinVar | [VCV1209001](https://www.ncbi.nlm.nih.gov/clinvar/variation/1209001/) |

**All HGVS expressions:** `NC_000015.10:g.76274417CTA[1]`, `NC_000015.9:g.76566758CTA[1]`, `NG_007077.2:g.42048TAG[1]`, `NM_000126.3:c.809_811delTAG`, `NM_000126.4:c.806TAG[1]`, `NM_000126.4:c.809_811del`, `NM_001127716.2:c.659TAG[1]`

## 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 11.789, GERP 1.74, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **in-frame indel**.
- CADD: **PHRED 19.01**. 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** — the release is built from a substitutions-only source, so it holds no microsatellite 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 **0.00562%** (nfe) · FAF95 0.00453% · FAF99 0.00413% · 66/1,174,472 in the highest group · 66/1,605,790 alleles overall — very rare (popmax 0.00562%, nfe).

*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 **270** lies in the 'domain ii' region.

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.Val270del falls in the domain ii 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-07-28.

**Submitter consensus:** conflicting (5 Likely pathogenic, 2 Uncertain significance, 1 Pathogenic, 1 Likely Pathogenic).

**Submission history:** 9 submissions (1992–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 1992-11-01 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-09-20 |
| Baylor Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-03-08 |
| GeneDx | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-11-19 |
| Fulgent Genetics, Fulgent Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-05-31 |
| Revvity Omics, Revvity | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-09-13 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Likely Pathogenic | criteria provided, single submitter | clinical testing | 2025-07-18 |
| Natera, Inc. | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-07-28 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-03-20 |

## Associated conditions {#conditions}

[Glutaric acidemia type 2A](https://sugi.bio/atlas/disease/glutaric-acidemia-type-2a/), [multiple acyl-CoA dehydrogenase deficiency](https://sugi.bio/atlas/disease/multiple-acyl-coa-dehydrogenase-deficiency/), [glutaric acidemia IIa](https://sugi.bio/atlas/disease/glutaric-acidemia-iia/).

**Reported phenotype names (ClinVar):** Glutaric acidemia type 2A, not provided, Multiple acyl-CoA dehydrogenase deficiency, Glutaric acidemia IIa, none provided, ETFA deficiency, 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.Val270=](/variant/etfa-p-val270), [ETFA p.His107fs](/variant/etfa-p-his107fs), [ETFA p.Ile108fs](/variant/etfa-p-ile108fs), [ETFA c.37_39+1del](/variant/etfa-c-37-39-plus-1del), [ETFA p.Glu198fs](/variant/etfa-p-glu198fs), [MADD p.Ser1178fs](/variant/madd-p-ser1178fs), [MADD p.Glu270Gln](/variant/madd-p-glu270gln), [ETFA c.817-12_817-11del](/variant/etfa-c-817-minus-12-817-minus-11del).

### 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 1209001). 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.*