# NM_000126.4(ETFA):c.20C>T (p.Pro7Leu)

https://sugi.bio/variant/etfa-p-pro7leu

## Summary

**ETFA p.Pro7Leu (c.20C>T)** is classified **Conflicting classifications of pathogenicity** in ETFA (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-03-05). AlphaMissense: likely benign (0.194); Ultra-rare (popmax 0.053%, nfe); Associated with multiple acyl-CoA dehydrogenase deficiency.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs557160401 · 7 submitters · 1 linked condition · AlphaMissense likely benign · ultra-rare (popmax 0.053%, 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 7 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.Pro7Leu |
| Coding change (HGVS c.) | c.20C>T |
| MANE Select transcript | [NM_000126](https://www.ncbi.nlm.nih.gov/nuccore/NM_000126) |
| dbSNP | [rs557160401](https://www.ncbi.nlm.nih.gov/snp/rs557160401/) |
| Variant type | single nucleotide variant |
| Location | chr15:76311369-76311369 (GRCh38) |
| ClinVar | [VCV203689](https://www.ncbi.nlm.nih.gov/clinvar/variation/203689/) |

**All HGVS expressions:** `NC_000015.10:g.76311369G>A`, `NC_000015.9:g.76603710G>A`, `NG_007077.2:g.5101C>T`, `NM_000126.4:c.20C>T`, `NM_001127716.2:c.20C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.194)
- REVEL 0.154 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -3.872 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 5.773, GERP 1.28, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 18.73**. 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.*
- Regional missense constraint: **o/e 0.86** across the covering region of the MANE Select transcript (76,216,562–76,311,388), spanning 94,826 bp. Chi-square p 0.0051. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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 **0.053%** (nfe) · FAF95 0.0495% · FAF99 0.0481% · 612/1,154,142 in the highest group · 642/1,562,322 alleles overall — ultra-rare (popmax 0.053%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.053% | 1,886 |
| Remaining individuals (not grpmax-eligible) | 0.0281% | 3,562 |
| African / African-American | 0.00947% | 10,564 |
| Finnish (not grpmax-eligible) | 0.00685% | 14,601 |
| Admixed American | 0.00379% | 26,382 |

*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}


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.


### 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 2025-03-05.

**Submitter consensus:** conflicting (6 Uncertain significance, 1 Likely benign).

**Submission history:** 7 submissions (2018–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-09-24 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-11-15 |
| Natera, Inc. | Uncertain significance | no assertion criteria provided | clinical testing | 2020-09-16 |
| Breakthrough Genomics, Breakthrough Genomics | Uncertain significance | criteria provided, single submitter | not provided |  |
| Mayo Clinic Laboratories, Mayo Clinic | Likely benign | criteria provided, single submitter | clinical testing | 2025-03-05 |
| CeGaT Center for Human Genetics Tuebingen | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-03-01 |

## 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, not provided, none provided, Glutaric aciduria, type 2, Glutaric acidemia type II, GA 2, Glutaric Acidemia type 2, ETHYLMALONIC-ADIPICACIDURIA, GA II.

## Same-residue context {#hotspot}

Residue **7** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [ETFA p.Pro7fs](/variant/etfa-p-pro7fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related ETFA variant pages (same residue, condition, or type): [ETFA p.Pro7=](/variant/etfa-p-pro7), [ETFA c.186+1G>A](/variant/etfa-c-186-plus-1g-a), [ETFA c.39+1G>A](/variant/etfa-c-39-plus-1g-a), [ETFA c.451+1G>A](/variant/etfa-c-451-plus-1g-a), [ETFA c.452-2A>G](/variant/etfa-c-452-minus-2a-g), [ETFA c.664+1G>A](/variant/etfa-c-664-plus-1g-a), [ETFA c.665-1G>A](/variant/etfa-c-665-minus-1g-a), [ETFA p.Arg122Lys](/variant/etfa-p-arg122lys).

### 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 203689). 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.*