# NM_018196.4(TMLHE):c.961_962del (p.Ile321fs)

https://sugi.bio/variant/tmlhe-p-ile321fs

## Summary

**TMLHE p.Ile321fs (c.961_962del)** is classified **Pathogenic** in TMLHE (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-05-04). Very rare (popmax 0.00176%, sas); Associated with epsilon-trimethyllysine hydroxylase deficiency.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs782624357 · 3 submitters · 1 linked condition · very rare (popmax 0.00176%, sas)

## For patients & families {#patients}

This is a change in the TMLHE gene that is considered disease-causing, submitted by 3 submitters, and is linked to epsilon-trimethyllysine hydroxylase 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.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [TMLHE](https://sugi.bio/atlas/gene/TMLHE/) |
| Protein change (HGVS p.) | p.Ile321fs |
| Coding change (HGVS c.) | c.961_962del |
| MANE Select transcript | [NM_018196](https://www.ncbi.nlm.nih.gov/nuccore/NM_018196) |
| dbSNP | [rs782624357](https://www.ncbi.nlm.nih.gov/snp/rs782624357/) |
| Variant type | Microsatellite |
| Location | chrX:155506931-155506932 (GRCh38) |
| ClinVar | [VCV225231](https://www.ncbi.nlm.nih.gov/clinvar/variation/225231/) |

**All HGVS expressions:** `NC_000023.10:g.154736592AT[1]`, `NC_000023.11:g.155506931AT[1]`, `NG_021318.1:g.111028AT[1]`, `NM_001184797.2:c.961_962del`, `NM_018196.4:c.961_962del`

## 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 1.437, GERP -0.119, phastCons 1 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 6 of 8**, so the transcript is predicted to undergo NMD.
- 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 **0.00176%** (sas) · 1/56,923 in the highest group · 1/1,209,172 alleles overall — very rare (popmax 0.00176%, sas).

*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}

**TMLHE** population constraint: ClinGen dosage — haploinsufficiency 1/3, triplosensitivity 0/3. *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):

- **autism spectrum disorder** — Disputed (XL)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 89.10, 85% of residues very-high.

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

*Describes the biological roles of TMLHE (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:** TMLHE's established molecular role includes trimethyllysine dioxygenase activity.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Carnitine synthesis](https://reactome.org/content/detail/R-HSA-71262) | other |

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

**Molecular function:** trimethyllysine dioxygenase activity.

**Biological process:** carnitine biosynthetic process.

## Clinical significance {#significance}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2022-05-04.

**Submitter consensus:** conflicting (2 Pathogenic, 1 risk factor).

**Submission history:** 3 submissions (2016–2022); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | risk factor | no assertion criteria provided | literature only | 2016-07-27 |
| Mendelics | Pathogenic | criteria provided, single submitter | clinical testing | 2022-05-04 |
| Baylor Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2017-09-01 |

## Associated conditions {#conditions}

[epsilon-trimethyllysine hydroxylase deficiency](https://sugi.bio/atlas/disease/epsilon-trimethyllysine-hydroxylase-deficiency/).

**Reported phenotype names (ClinVar):** Epsilon-trimethyllysine hydroxylase deficiency, Autism, susceptibility to, X-linked 6.

## Similar variants {#similar}

Related TMLHE variant pages (same residue, condition, or type): [TMLHE p.Ile321=](/variant/tmlhe-p-ile321), [TMLHE p.Arg77Ter](/variant/tmlhe-p-arg77ter), [TMLHE p.Arg93His](/variant/tmlhe-p-arg93his), [TMLHE p.Glu175Lys](/variant/tmlhe-p-glu175lys), [TMLHE p.Glu369Asp](/variant/tmlhe-p-glu369asp), [TMLHE p.Thr265Ile](/variant/tmlhe-p-thr265ile), [TMLHE p.Trp53Ter](/variant/tmlhe-p-trp53ter), [TMLHE p.Trp75Ter](/variant/tmlhe-p-trp75ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 225231). 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.*