# NM_000260.4(MYO7A):c.2558G>A (p.Arg853His)

https://sugi.bio/variant/myo7a-p-arg853his

## Summary

**MYO7A p.Arg853His (c.2558G>A)** is classified **Likely pathogenic** in MYO7A (ClinVar, Expert panel, 15 submitters; last evaluated 2022-10-31). AlphaMissense: ambiguous (0.3623); Very rare (popmax 0.00246%, eas); Associated with nonsyndromic genetic hearing loss.

**At a glance:** Likely pathogenic · review: Expert panel · rsID rs111033437 · 15 submitters · 5 linked conditions · AlphaMissense ambiguous · very rare (popmax 0.00246%, eas)

## For patients & families {#patients}

This is a change in the MYO7A gene that is considered likely disease-causing, submitted by 15 submitters, and is linked to nonsyndromic genetic hearing loss.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Autosomal recessive, X-linked recessive |
| Age of onset (of this condition) | Infancy, Neonatal |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | MYO7A is a diagnostic-grade gene on 4 Genomics England panels |

**Commonly reported features of Rare non-syndromic genetic deafness** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Prelingual sensorineural hearing impairment — Frequent (79-30%)
- Progressive sensorineural hearing impairment — Frequent (79-30%)
- Delayed speech and language development — Frequent (79-30%)
- Abnormal speech discrimination — Frequent (79-30%)
- Postlingual sensorineural hearing impairment — Frequent (79-30%)
- Profound sensorineural hearing impairment — Frequent (79-30%)
- Conductive hearing impairment — Occasional (29-5%)
- High-frequency hearing impairment — Occasional (29-5%)

**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.Arg853His |
| Coding change (HGVS c.) | c.2558G>A |
| MANE Select transcript | [NM_000260](https://www.ncbi.nlm.nih.gov/nuccore/NM_000260) |
| dbSNP | [rs111033437](https://www.ncbi.nlm.nih.gov/snp/rs111033437/) |
| Variant type | single nucleotide variant |
| Location | chr11:77179925-77179925 (GRCh38) |
| ClinVar | [VCV43186](https://www.ncbi.nlm.nih.gov/clinvar/variation/43186/) |

**All HGVS expressions:** `LRG_1420:g.56680G>A`, `LRG_1420t1:c.2558G>A`, `NC_000011.10:g.77179925G>A`, `NC_000011.9:g.76890971G>A`, `NG_009086.2:g.56680G>A`, `NM_000260.4(MYO7A):c.2558G>A`, `NM_000260.4:c.2558G>A`, `NM_001127180.2:c.2558G>A`, `NM_001369365.1:c.2525G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **ambiguous** (0.3623) — no call either way
- REVEL 0.741 (pathogenic-leaning)
- SaProt LLR -12.906 (damaging)
- → **In-silico consensus:** REVEL and SaProt both call this damaging; AlphaMissense is indeterminate
- Conservation: phyloP 11.67, GERP 1.76, phastCons 1 — highly conserved
- CADD: **PHRED 28.5**. 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: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for MYO7A (3,056 scored positions, the nearest 11 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **0.00246%** (eas) · FAF95 0.000371% · FAF99 0.000269% · 1/40,686 in the highest group · 11/1,531,882 alleles overall — very rare (popmax 0.00246%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00246% | 40,686 |
| Remaining individuals (not grpmax-eligible) | 0.00168% | 59,414 |
| European (non-Finnish) | 0.000788% | 126,880 |

*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 **853** lies in the iq 5 domain; a UniProt-annotated variant site (in dfna11; disturb calmodulin/myo7a binding).

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.Arg853His falls in the iq 5 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 Expert panel *(reviewed by expert panel)*, last evaluated 2022-10-31.

**Submitter consensus:** conflicting (6 Likely pathogenic, 5 Pathogenic, 3 Uncertain significance, 1 Likely Pathogenic).

**Submission history:** 15 submissions (2013–2026); classifications have differed over time.

**ClinGen expert panel:** Likely Pathogenic — Hearing Loss VCEP (nonsyndromic genetic deafness). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `PP1_Strong`, `PM2_Supporting`, `PS4_Supporting`, `PP3`.
*Considered but not met:* `PM5`.
Inheritance: Autosomal dominant inheritance.

> **Curation rationale (ClinGen, verbatim):** The c.2558G>A variant in MYO7A is a missense variant predicted to cause substitution of arginine by histidine at amino acid 853. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.741, which is above the threshold of 0.7, evidence that correlates with impact to MYO7A function (PP3). This variant has been reported in 3 probands/families with hearing loss (PS4_Supporting; PMIDs: 26969326, 32097363, ClinVar SCV: SCV000059742.6, LMM). The variant has been reported to segregate with nonsyndromic genetic hearing loss in 10 affected family members from 1 family (PP1_Strong; PMID: 32097363). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant nonsyndromic genetic hearing loss based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PP1_S, PS4_P, PM2_P, PP3 (Hearing Loss VCEP specifications version 2; 10/31/2022).
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50007 · approved 2022-10-31 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/c33ae219-757e-4113-a157-ae454a79015c).*
*These are ClinGen's applied codes, reported verbatim — Sugi Variant does not re-tally or combine them into its own classification.*

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-10-31 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2023-09-07 |
| Natera, Inc. | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-10-13 |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Uncertain significance | criteria provided, single submitter | clinical testing | 2013-11-03 |
| ClinGen Hearing Loss Variant Curation Expert Panel | Likely pathogenic | reviewed by expert panel | curation | 2022-10-31 |
| PreventionGenetics, part of Exact Sciences | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-09-14 |
| Knight Diagnostic Laboratories, Oregon Health and Sciences University | Likely pathogenic | criteria provided, single submitter | clinical testing | 2019-11-27 |
| National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center | Likely pathogenic | criteria provided, single submitter | research | 2018-04-24 |
| Ambry Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2025-06-20 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2026-01-18 |
| Variantyx, Inc. | Likely Pathogenic | criteria provided, single submitter | clinical testing | 2026-01-05 |
| The Shared Resource Centre "Genome", Research Centre for Medical Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2022-11-10 |
| Eurofins Ntd Llc (ga) | Uncertain significance | criteria provided, single submitter | clinical testing | 2015-03-20 |
| Clinical Genetics Laboratory, University Hospital Schleswig-Holstein | Pathogenic | no assertion criteria provided | clinical testing | 2024-02-22 |
| Blueprint Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-09-25 |

## Associated conditions {#conditions}

[nonsyndromic genetic hearing loss](https://sugi.bio/atlas/disease/nonsyndromic-genetic-hearing-loss/), [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):** Nonsyndromic genetic hearing loss, not specified, not provided, Autosomal dominant nonsyndromic hearing loss 11, Autosomal recessive nonsyndromic hearing loss 2, Usher syndrome type 1, MYO7A-related disorder, Usher syndrome type 1B, Inborn genetic diseases, MYO7A-related disorders.

## Same-residue context {#hotspot}

Residue **853** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [MYO7A p.Arg853Cys](/variant/myo7a-p-arg853cys), [MYO7A p.Arg853Ser](/variant/myo7a-p-arg853ser). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related MYO7A variant pages (same residue, condition, or type): [MYO7A p.Arg853Cys](/variant/myo7a-p-arg853cys), [MYO7A p.Arg853Ser](/variant/myo7a-p-arg853ser), [MYO7A p.Arg853Leu](/variant/myo7a-p-arg853leu), [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).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 43186). 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.*