# NM_000260.4(MYO7A):c.2617C>T (p.Arg873Trp)

https://sugi.bio/variant/myo7a-p-arg873trp

## Summary

**MYO7A p.Arg873Trp (c.2617C>T)** is classified **Conflicting classifications of pathogenicity** in MYO7A (ClinVar, Conflicting submitters, 12 submitters; last evaluated 2026-01-26). AlphaMissense: ambiguous (0.395); Rare (popmax 0.137%, nfe); Associated with Meniere disease.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs200454015 · 12 submitters · 5 linked conditions · AlphaMissense ambiguous · rare (popmax 0.137%, 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 12 submitters, and is linked to Meniere disease.

*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 | 31 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | MYO7A is a diagnostic-grade gene on 4 Genomics England panels |

**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.Arg873Trp |
| Coding change (HGVS c.) | c.2617C>T |
| MANE Select transcript | [NM_000260](https://www.ncbi.nlm.nih.gov/nuccore/NM_000260) |
| dbSNP | [rs200454015](https://www.ncbi.nlm.nih.gov/snp/rs200454015/) |
| Variant type | single nucleotide variant |
| Location | chr11:77180404-77180404 (GRCh38) |
| ClinVar | [VCV43187](https://www.ncbi.nlm.nih.gov/clinvar/variation/43187/) |

**All HGVS expressions:** `LRG_1420:g.57159C>T`, `LRG_1420t1:c.2617C>T`, `NC_000011.10:g.77180404C>T`, `NC_000011.9:g.76891450C>T`, `NG_009086.2:g.57159C>T`, `NM_000260.4:c.2617C>T`, `NM_001127180.2:c.2617C>T`, `NM_001369365.1:c.2584C>T`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; REVEL and SaProt both call this damaging; AlphaMissense is indeterminate — descriptive only.

- AlphaMissense **ambiguous** (0.395) — no call either way
- REVEL 0.821 (moderately pathogenic-leaning)
- SaProt LLR -13.329 (damaging)
- → **In-silico consensus:** REVEL and SaProt both call this damaging; AlphaMissense is indeterminate
- Conservation: phyloP 1.097, GERP -0.597, phastCons 1 — weakly conserved position
- CADD: **PHRED 25.9**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 0.95** across the covering region of the MANE Select transcript (77,130,635–77,214,693), spanning 84,058 bp. Chi-square p 0.0065. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.137%** (nfe) · FAF95 0.132% · FAF99 0.13% · 1,621/1,179,548 in the highest group · 1,871/1,611,950 alleles overall — rare (popmax 0.137%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.25% | 399 |
| European (non-Finnish) (grpmax) | 0.137% | 728 |
| Remaining individuals (not grpmax-eligible) | 0.0929% | 1,077 |
| African / African-American | 0.0307% | 3,262 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00676% | 14,800 |
| Admixed American | 0.00668% | 14,979 |
| East Asian | 0.00446% | 22,425 |
| South Asian | 0.0044% | 22,721 |

Finnish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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 **873** lies in the 'sah' region.

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.Arg873Trp falls in the sah region.


### 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 2026-01-26.

**Submitter consensus:** conflicting (8 Uncertain significance, 5 Likely benign, 1 Benign).

**Submission history:** 14 submissions (2012–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Natera, Inc. | Likely benign | no assertion criteria provided | clinical testing | 2020-04-16 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-11-03 |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Likely benign | criteria provided, single submitter | clinical testing | 2012-02-09 |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2017-04-27 |
| Myriad Genetics, Inc. | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-11-03 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2024-08-16 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-26 |
| Mendelics | Benign | criteria provided, single submitter | clinical testing | 2019-05-28 |
| Centre for Mendelian Genomics, University Medical Centre Ljubljana | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-12-20 |
| Otology & Neurotology- Genomics of vestibular disorders (CTS-495), Jose Antonio López Escámez, Centro Pfizer - Universidad de Granada - Junta de Andalucía de Genómica e Investigación Oncológica (GENYO) | Uncertain significance | criteria provided, single submitter | case-control | 2020-12-14 |
| Eurofins Ntd Llc (ga) | Uncertain significance | criteria provided, single submitter | clinical testing | 2014-10-16 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-22 |

## Associated conditions {#conditions}

[Meniere disease](https://sugi.bio/atlas/disease/meniere-disease/), [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/), [autosomal dominant nonsyndromic hearing loss 11](https://sugi.bio/atlas/disease/autosomal-dominant-nonsyndromic-hearing-loss-11/), [Usher syndrome type 1B](https://sugi.bio/atlas/disease/usher-syndrome-type-1b/).

**Reported phenotype names (ClinVar):** Meniere disease, not specified, not provided, Autosomal recessive nonsyndromic hearing loss 2, Usher syndrome type 1, Autosomal dominant nonsyndromic hearing loss 11, Usher syndrome type 1B, MYO7A-related disorder, MYO7A-related disorders, Ménière's disease.

## Similar variants {#similar}

Related MYO7A variant pages (same residue, condition, or type): [MYO7A p.Arg873Gln](/variant/myo7a-p-arg873gln), [MYO7A p.Arg873=](/variant/myo7a-p-arg873), [MYO7A p.Ala1288Pro](/variant/myo7a-p-ala1288pro), [MYO7A p.Arg1168Gln](/variant/myo7a-p-arg1168gln), [MYO7A p.Arg1873Gln](/variant/myo7a-p-arg1873gln), [MYO7A p.Arg395Cys](/variant/myo7a-p-arg395cys), [MYO7A p.Arg668Cys](/variant/myo7a-p-arg668cys), [MYO7A p.Arg853His](/variant/myo7a-p-arg853his).

### 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 43187). 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.*