# NM_004092.4(ECHS1):c.582_589delinsCGGTGACT (p.Arg197Trp)

https://sugi.bio/variant/echs1-p-arg197trp

## Summary

**ECHS1 p.Arg197Trp (c.582_589delinsCGGTGACT)** is classified **Likely pathogenic** in ECHS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-06). No gnomAD frequency available for this variant.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs2133440581 · 1 submitter · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the ECHS1 gene that is considered likely disease-causing, submitted by 1 submitter.

*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 | [ECHS1](https://sugi.bio/atlas/gene/ECHS1/) |
| Protein change (HGVS p.) | p.Arg197Trp |
| Coding change (HGVS c.) | c.582_589delinsCGGTGACT |
| MANE Select transcript | [NM_004092](https://www.ncbi.nlm.nih.gov/nuccore/NM_004092) |
| dbSNP | [rs2133440581](https://www.ncbi.nlm.nih.gov/snp/rs2133440581/) |
| Variant type | Indel |
| Location | chr10:133366919-133366926 (GRCh38) |
| ClinVar | [VCV1194776](https://www.ncbi.nlm.nih.gov/clinvar/variation/1194776/) |

**All HGVS expressions:** `NC_000010.10:g.135180423_135180430delinsAGTCACCG`, `NC_000010.11:g.133366919_133366926delinsAGTCACCG`, `NG_042077.1:g.11479_11486delinsCGGTGACT`, `NM_004092.3:c.582_589delTGGTGACCinsCGGTGACT`, `NM_004092.4:c.582_589delinsCGGTGACT`

## 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 5.723, phastCons 1 — highly conserved position (PP3-type support)
- Regional missense constraint: **o/e 0.96** across the covering region of the MANE Select transcript (133,362,871–133,373,333), spanning 10,462 bp. Chi-square p 0.4. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no indel variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**ECHS1** population constraint: LOEUF 0.907, pLI 0.0009322, missense-Z 0.70813. *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):

- **Leigh syndrome** — Definitive (AR)
- **mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 91.54, 85% of residues very-high.

**6 experimental structure(s)** (PDB): [2HW5](https://www.rcsb.org/structure/2HW5), [8ZRU](https://www.rcsb.org/structure/8ZRU), [8ZRV](https://www.rcsb.org/structure/8ZRV), [8ZRW](https://www.rcsb.org/structure/8ZRW), [8ZRX](https://www.rcsb.org/structure/8ZRX), [8ZRY](https://www.rcsb.org/structure/8ZRY).

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

*Describes the biological roles of ECHS1 (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:** ECHS1's established molecular role includes enoyl-CoA hydratase activity. In Reactome, ECHS1 is annotated in disease pathway(s) including **Mitochondrial short-chain enoyl-CoA hydratase deficiency 1**.

**Disease mechanism (Reactome):** ECHS1 loss or alteration is curated in [Mitochondrial short-chain enoyl-CoA hydratase deficiency 1](https://reactome.org/content/detail/R-HSA-9916720).

### Pathways affected {#pathways}

ECHS1 participates in **7 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Mitochondrial short-chain enoyl-CoA hydratase deficiency 1](https://reactome.org/content/detail/R-HSA-9916720) | curated |
| [Beta oxidation of butanoyl-CoA to acetyl-CoA](https://reactome.org/content/detail/R-HSA-77352) | curated |
| [Beta oxidation of decanoyl-CoA to octanoyl-CoA-CoA](https://reactome.org/content/detail/R-HSA-77346) | curated |
| [Beta oxidation of hexanoyl-CoA to butanoyl-CoA](https://reactome.org/content/detail/R-HSA-77350) | curated |
| [Beta oxidation of lauroyl-CoA to decanoyl-CoA-CoA](https://reactome.org/content/detail/R-HSA-77310) | curated |
| [Beta oxidation of octanoyl-CoA to hexanoyl-CoA](https://reactome.org/content/detail/R-HSA-77348) | curated |
| [Branched-chain amino acid catabolism](https://reactome.org/content/detail/R-HSA-70895) | curated |

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

**Molecular function:** enoyl-CoA hydratase activity, 3-hydroxypropionyl-CoA dehydratase activity.

**Biological process:** L-valine catabolic process, fatty acid beta-oxidation.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-10-06.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-10-06 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related ECHS1 variant pages (same residue, condition, or type): [ECHS1 p.Arg197Gly](/variant/echs1-p-arg197gly), [ECHS1 p.Ile198_Lys204delinsTer](/variant/echs1-p-ile198-lys204delinster), [ECHS1 p.Val237Gly](/variant/echs1-p-val237gly).

### 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 1194776). 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.*