# NM_001354604.2(MITF):c.896_897del (p.Thr299fs)

https://sugi.bio/variant/mitf-p-thr299fs

## Summary

**MITF p.Thr299fs (c.896_897del)** is classified **Pathogenic** in MITF (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-12). Very rare (popmax 8.48e-05%, nfe); Associated with Waardenburg syndrome type 2A.

**At a glance:** Pathogenic · review: Multiple submitters · 2 submitters · 3 linked conditions · very rare (popmax 8.48e-05%, nfe)

## For patients & families {#patients}

This is a change in the MITF gene that is considered disease-causing, submitted by 2 submitters, and is linked to Waardenburg syndrome 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.*

|  |  |
| --- | --- |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0005521/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [MITF](https://sugi.bio/atlas/gene/MITF/) |
| Protein change (HGVS p.) | p.Thr299fs |
| Coding change (HGVS c.) | c.896_897del |
| MANE Select transcript | [NM_001354604](https://www.ncbi.nlm.nih.gov/nuccore/NM_001354604) |
| Variant type | Microsatellite |
| Location | chr3:69951825-69951826 (GRCh38) |
| ClinVar | [VCV3601257](https://www.ncbi.nlm.nih.gov/clinvar/variation/3601257/) |

**All HGVS expressions:** `LRG_776:g.217344CA[1]`, `LRG_776t1:c.573_574CA[1]`, `NC_000003.11:g.70000976CA[1]`, `NC_000003.12:g.69951825CA[1]`, `NG_011631.1:g.217344CA[1]`, `NM_000248.4:c.575_576del`, `NM_001184967.2:c.725-3_725-2del`, `NM_001354604.2:c.896_897del`, `NM_001354605.2:c.893_894del`, `NM_001354606.2:c.878-3_878-2del`, `NM_001354607.2:c.830-3_830-2del`, `NM_001354608.2:c.725-3_725-2del`, `NM_006722.3:c.878-3_878-2del`, `NM_198158.3:c.560-3_560-2del`, `NM_198159.3:c.881-3_881-2del`, `NM_198177.3:c.833-3_833-2del`, `NM_198178.3:c.392-3_392-2del`

## 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 7.655, GERP 2.15, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene (constraint LOEUF 0.482, pLI 0.99203), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 7 of 10**, 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 **8.48e-05%** (nfe) · 1/1,179,588 in the highest group · 1/1,613,384 alleles overall — very rare (popmax 8.48e-05%, 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}

**MITF** population constraint: LOEUF 0.482, pLI 0.99203, missense-Z 1.0386; ClinGen dosage — haploinsufficiency 3/3, 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):

- **Waardenburg syndrome type 2** — Definitive (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 62.25, 21% of residues very-high.

**12 experimental structure(s)** (PDB): [4C7N](https://www.rcsb.org/structure/4C7N), [7D8R](https://www.rcsb.org/structure/7D8R), [7D8S](https://www.rcsb.org/structure/7D8S), [7D8T](https://www.rcsb.org/structure/7D8T), [7EOD](https://www.rcsb.org/structure/7EOD), [8E1D](https://www.rcsb.org/structure/8E1D).

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

*Describes the biological roles of MITF (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:** MITF's established molecular role includes RNA polymerase II cis-regulatory region sequence-specific DNA binding.


### Pathways affected {#pathways}

MITF participates in **10 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [SUMOylation of transcription factors](https://reactome.org/content/detail/R-HSA-3232118) | curated |
| [Regulation of MITF-M dependent genes involved in invasion](https://reactome.org/content/detail/R-HSA-9854909) | other |
| [Regulation of MITF-M dependent genes involved in metabolism](https://reactome.org/content/detail/R-HSA-9854907) | other |
| [Regulation of MITF-M-dependent genes involved in DNA replication, damage repair and senescence](https://reactome.org/content/detail/R-HSA-9825895) | other |
| [Regulation of MITF-M-dependent genes involved in apoptosis](https://reactome.org/content/detail/R-HSA-9824594) | other |
| [Regulation of MITF-M-dependent genes involved in cell cycle and proliferation](https://reactome.org/content/detail/R-HSA-9825892) | other |
| [Regulation of MITF-M-dependent genes involved in extracellular matrix, focal adhesion and epithelial-to-mesenchymal transition](https://reactome.org/content/detail/R-HSA-9926550) | other |
| [Regulation of MITF-M-dependent genes involved in lysosome biogenesis and autophagy](https://reactome.org/content/detail/R-HSA-9857377) | other |
| [Regulation of MITF-M-dependent genes involved in pigmentation](https://reactome.org/content/detail/R-HSA-9824585) | other |
| [Transcriptional and post-translational regulation of MITF-M expression and activity](https://reactome.org/content/detail/R-HSA-9856649) | electronic |

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

**Molecular function:** RNA polymerase II cis-regulatory region sequence-specific DNA binding, DNA-binding transcription activator activity, RNA polymerase II-specific, E-box binding.

**Biological process:** negative regulation of transcription by RNA polymerase II, regulation of DNA-templated transcription, positive regulation of gene expression, negative regulation of cell migration, positive regulation of DNA-templated transcription, positive regulation of transcription by RNA polymerase II.

## Clinical significance {#significance}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-06-12.

**Submitter consensus:** unanimous (2/2 Pathogenic).

**Submission history:** 2 submissions (2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Institute of Rare Diseases, West China Hospital, Sichuan University | Pathogenic | criteria provided, single submitter | research | 2025-01-09 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-06-12 |

## Associated conditions {#conditions}

[Waardenburg syndrome type 2A](https://sugi.bio/atlas/disease/waardenburg-syndrome-type-2a/), [Tietz syndrome](https://sugi.bio/atlas/disease/tietz-syndrome/), [melanoma, cutaneous malignant, susceptibility to, 8](https://sugi.bio/atlas/disease/melanoma-cutaneous-malignant-susceptibility-to-8/).

**Reported phenotype names (ClinVar):** Waardenburg syndrome type 2A, Melanoma, cutaneous malignant, susceptibility to, 8, Tietz syndrome, WAARDENBURG SYNDROME WITHOUT DYSTOPIA CANTHORUM, Cutaneous malignant melanoma 8, MELANOMA AND RENAL CELL CARCINOMA, SUSCEPTIBILITY TO, HYPOPIGMENTATION/DEAFNESS OF TIETZ, TIETZ ALBINISM-DEAFNESS SYNDROME, ALBINISM-DEAFNESS OF TIETZ.

## Similar variants {#similar}

Related MITF variant pages (same residue, condition, or type): [MITF p.Arg324del](/variant/mitf-p-arg324del), [MITF p.Ser512del](/variant/mitf-p-ser512del), [MITF p.Ala294fs](/variant/mitf-p-ala294fs), [MITF p.Glu300fs](/variant/mitf-p-glu300fs), [MITF p.Ser216fs](/variant/mitf-p-ser216fs), [MITF p.Ser258fs](/variant/mitf-p-ser258fs), [MITF p.Leu436_Gln437insLeu](/variant/mitf-p-leu436-gln437insleu), [MITF p.Thr299Ala](/variant/mitf-p-thr299ala).

### 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 3601257). 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.*