# NM_000260.4(MYO7A):c.5488dup (p.Glu1830fs)

https://sugi.bio/variant/myo7a-p-glu1830fs

## Summary

**MYO7A p.Glu1830fs (c.5488dup)** is classified **Likely pathogenic** in MYO7A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-05-29). No gnomAD frequency available for this variant; Associated with MYO7A-related disorder.

**At a glance:** Likely pathogenic · review: Multiple submitters · rsID rs1555105135 · 3 submitters · 4 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the MYO7A gene that is considered likely disease-causing, submitted by 3 submitters, and is linked to MYO7A-related disorder.

*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 | [MYO7A](https://sugi.bio/atlas/gene/MYO7A/) |
| Protein change (HGVS p.) | p.Glu1830fs |
| Coding change (HGVS c.) | c.5488dup |
| MANE Select transcript | [NM_000260](https://www.ncbi.nlm.nih.gov/nuccore/NM_000260) |
| dbSNP | [rs1555105135](https://www.ncbi.nlm.nih.gov/snp/rs1555105135/) |
| Variant type | Duplication |
| Location | chr11:77205468-77205469 (GRCh38) |
| ClinVar | [VCV553211](https://www.ncbi.nlm.nih.gov/clinvar/variation/553211/) |

**All HGVS expressions:** `LRG_1420:g.82224dup`, `LRG_1420t1:c.5488dup`, `NC_000011.10:g.77205469dup`, `NC_000011.9:g.76916514dup`, `NG_009086.2:g.82224dup`, `NM_000260.3:c.5488dup`, `NM_000260.3:c.5488dupG`, `NM_000260.4:c.5488dup`, `NM_001127180.2:c.5374dup`, `NM_001369365.1:c.5341dup`

## 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 -6.041, GERP -2.55 — fast-evolving / accelerated position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.995, pLI 2.4072e-62. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 40 of 49**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication 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}

**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 **1830** lies in the myth4 2 domain; an α-helix.

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.Glu1830fs falls in the myth4 2 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}

**Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-05-29.

**Submitter consensus:** unanimous (3/3 Likely pathogenic).

**Submission history:** 3 submissions (2017–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-07-25 |
| Counsyl | Likely pathogenic | no assertion criteria provided | clinical testing | 2017-08-08 |
| Natera, Inc. | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-05-29 |

## Associated conditions {#conditions}

[MYO7A-related disorder](https://sugi.bio/atlas/disease/myo7a-related-disorder/), [Usher syndrome type 1](https://sugi.bio/atlas/disease/usher-syndrome-type-1/), [autosomal recessive nonsyndromic hearing loss 2](https://sugi.bio/atlas/disease/autosomal-recessive-nonsyndromic-hearing-loss-2/), [Usher syndrome type 1B](https://sugi.bio/atlas/disease/usher-syndrome-type-1b/).

**Reported phenotype names (ClinVar):** MYO7A-related disorder, Autosomal recessive nonsyndromic hearing loss 2, Usher syndrome type 1, Usher syndrome type 1B, DEAFNESS, AUTOSOMAL RECESSIVE 2, NEUROSENSORY NONSYNDROMIC RECESSIVE DEAFNESS 2, RETINITIS PIGMENTOSA AND CONGENITAL DEAFNESS, MYO7A-related disorders, Usher syndrome type IB.

## Same-residue context {#hotspot}

Residue **1830** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [MYO7A p.Glu1830Ter](/variant/myo7a-p-glu1830ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related MYO7A variant pages (same residue, condition, or type): [MYO7A p.Glu1830Ter](/variant/myo7a-p-glu1830ter), [MYO7A p.Asp365fs](/variant/myo7a-p-asp365fs), [MYO7A p.Gly1842fs](/variant/myo7a-p-gly1842fs), [MYO7A p.His133fs](/variant/myo7a-p-his133fs), [MYO7A p.Ile454fs](/variant/myo7a-p-ile454fs), [MYO7A p.Ile94fs](/variant/myo7a-p-ile94fs), [MYO7A p.Leu1046fs](/variant/myo7a-p-leu1046fs), [MYO7A p.Lys1294fs](/variant/myo7a-p-lys1294fs).

### 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 553211). 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.*