# NM_000260.4(MYO7A):c.799AAG[2] (p.Lys269del)

https://sugi.bio/variant/myo7a-p-lys269del

## Summary

**MYO7A p.Lys269del (c.799AAG[2])** is classified **Conflicting classifications of pathogenicity** in MYO7A (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-08-22). Very rare (popmax 0.000339%, nfe); Associated with Usher syndrome type 1B.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs781896482 · 2 submitters · 1 linked condition · very rare (popmax 0.000339%, nfe)

## For patients & families {#patients}

This is a change in the MYO7A gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters, and is linked to Usher syndrome type 1B.

*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 | 3 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0005436/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [MYO7A](https://sugi.bio/atlas/gene/MYO7A/) |
| Protein change (HGVS p.) | p.Lys269del |
| Coding change (HGVS c.) | c.799AAG[2] |
| MANE Select transcript | [NM_000260](https://www.ncbi.nlm.nih.gov/nuccore/NM_000260) |
| dbSNP | [rs781896482](https://www.ncbi.nlm.nih.gov/snp/rs781896482/) |
| Variant type | Microsatellite |
| Location | chr11:77157340-77157342 (GRCh38) |
| ClinVar | [VCV2137201](https://www.ncbi.nlm.nih.gov/clinvar/variation/2137201/) |

**All HGVS expressions:** `LRG_1420:g.34097AAG[2]`, `LRG_1420t1:c.799AAG[2]`, `NC_000011.10:g.77157342AAG[2]`, `NC_000011.9:g.76868388AAG[2]`, `NG_009086.2:g.34097AAG[2]`, `NM_000260.3:c.805_807delAAG`, `NM_000260.4:c.799AAG[2]`, `NM_001127180.2:c.799AAG[2]`, `NM_001369365.1:c.766AAG[2]`

## 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 2.251, GERP -3.51, phastCons 0.98 — highly conserved position (PP3-type support)
- Molecular consequence: **in-frame indel**.
- 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 **0.000339%** (nfe) · FAF95 7.9e-05% · FAF99 5.4e-05% · 4/1,179,274 in the highest group · 4/1,612,396 alleles overall — very rare (popmax 0.000339%, 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}

**MYO7A** population constraint: LOEUF 0.995, pLI 2.4072e-62, missense-Z 0.076546. *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):

- **Usher syndrome type 1** — Definitive (AR)
- **nonsyndromic genetic hearing loss** — Definitive (AD)

## Protein context {#protein}

Residue **269** lies in the myosin motor domain; a UniProt-annotated variant site (in ush1b).

AlphaFold model confidence (whole protein): pLDDT 77.73, 16% of residues very-high.

**1 experimental structure(s)** (PDB): [5MV9](https://www.rcsb.org/structure/5MV9).

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

*Describes the biological roles of MYO7A (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:** MYO7A's established molecular role includes microfilament motor activity. p.Lys269del falls in the myosin motor domain.


### Pathways affected {#pathways}

MYO7A participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [The canonical retinoid cycle in rods (twilight vision)](https://reactome.org/content/detail/R-HSA-2453902) | curated |
| [Sensory processing of sound by inner hair cells of the cochlea](https://reactome.org/content/detail/R-HSA-9662360) | electronic |
| [Sensory processing of sound by outer hair cells of the cochlea](https://reactome.org/content/detail/R-HSA-9662361) | electronic |

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

**Molecular function:** microfilament motor activity, calmodulin binding, spectrin binding, actin filament binding.

**Biological process:** lysosome organization, visual perception, sensory perception of sound, actin filament-based movement, sensory perception of light stimulus, equilibrioception.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2024-08-22.

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

**Submission history:** 2 submissions (2022–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-08-19 |
| Natera, Inc. | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-08-22 |

## Associated conditions {#conditions}

[Usher syndrome type 1B](https://sugi.bio/atlas/disease/usher-syndrome-type-1b/).

**Reported phenotype names (ClinVar):** Usher syndrome type 1B, not provided, Usher syndrome type IB, none provided.

## Same-residue context {#hotspot}

Residue **269** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [MYO7A p.Lys269fs](/variant/myo7a-p-lys269fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related MYO7A variant pages (same residue, condition, or type): [MYO7A p.Glu1716del](/variant/myo7a-p-glu1716del), [MYO7A p.Phe1963del](/variant/myo7a-p-phe1963del), [MYO7A p.Ser423fs](/variant/myo7a-p-ser423fs), [MYO7A p.Val1501fs](/variant/myo7a-p-val1501fs), [MYO7A c.3924+31_3924+46del](/variant/myo7a-c-3924-plus-31-3924-plus-46del), [MYO7A p.Ala601fs](/variant/myo7a-p-ala601fs), [MYO7A p.Lys269fs](/variant/myo7a-p-lys269fs), [MYO7A p.Thr54fs](/variant/myo7a-p-thr54fs).

### 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 2137201). 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.*