# NM_000260.4(MYO7A):c.1007G>A (p.Arg336His)

https://sugi.bio/variant/myo7a-p-arg336his

## Summary

**MYO7A p.Arg336His (c.1007G>A)** is classified **Likely benign** in MYO7A (ClinVar, Expert panel, 15 submitters; last evaluated 2024-11-20). AlphaMissense: likely benign (0.117); Rare (popmax 0.286%, nfe); Associated with Usher syndrome.

**At a glance:** Likely benign · review: Expert panel · rsID rs45629132 · 15 submitters · 6 linked conditions · AlphaMissense likely benign · rare (popmax 0.286%, nfe)

## For patients & families {#patients}

This is a change in the MYO7A gene that is classified as likely benign — not considered disease-causing, submitted by 15 submitters, and is linked to Usher syndrome.

*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 recessive |
| Age of onset (of this condition) | Childhood, Infancy, Neonatal |
| Prevalence | 1-9 / 100 000 (Worldwide) |
| Clinical trials | 19 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | MYO7A is a diagnostic-grade gene on 4 Genomics England panels |

**Commonly reported features of Usher syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Sensorineural hearing impairment — Very frequent (99-80%)
- Visual impairment — Very frequent (99-80%)
- Abnormal electroretinogram — Very frequent (99-80%)
- Progressive visual loss — Very frequent (99-80%)
- Blindness — Very frequent (99-80%)
- Nyctalopia — Very frequent (99-80%)
- Visual field defect — Very frequent (99-80%)
- Abnormal vestibular function — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0007843/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.Arg336His |
| Coding change (HGVS c.) | c.1007G>A |
| MANE Select transcript | [NM_000260](https://www.ncbi.nlm.nih.gov/nuccore/NM_000260) |
| dbSNP | [rs45629132](https://www.ncbi.nlm.nih.gov/snp/rs45629132/) |
| Variant type | single nucleotide variant |
| Location | chr11:77159450-77159450 (GRCh38) |
| ClinVar | [VCV43134](https://www.ncbi.nlm.nih.gov/clinvar/variation/43134/) |

**All HGVS expressions:** `LRG_1420:g.36205G>A`, `LRG_1420t1:c.1007G>A`, `NC_000011.10:g.77159450G>A`, `NC_000011.9:g.76870496G>A`, `NG_009086.2:g.36205G>A`, `NM_000260.4:c.1007G>A`, `NM_001127180.2:c.1007G>A`, `NM_001369365.1:c.974G>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.117)
- REVEL 0.734 (pathogenic-leaning) — differs from AlphaMissense
- SaProt LLR -9.367 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** REVEL calls this damaging; AlphaMissense and SaProt do not
- Conservation: phyloP 11.743, GERP 1.44, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 25.3**. 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 **0.286%** (nfe) · FAF95 0.277% · FAF99 0.274% · 2,854/996,858 in the highest group · 3,032/1,334,368 alleles overall — rare (popmax 0.286%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.286% | 349 |
| Remaining individuals (not grpmax-eligible) | 0.162% | 618 |
| African / African-American | 0.0768% | 1,301 |
| Admixed American | 0.0651% | 1,536 |
| Finnish (not grpmax-eligible) | 0.0367% | 2,726 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.0144% | 6,945 |
| East Asian | 0.00722% | 13,846 |
| South Asian | 0.00459% | 21,796 |

*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 **336** lies in the myosin motor domain.

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.Arg336His 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}

**Likely benign** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2024-11-20.

**Submitter consensus:** conflicting (11 Likely benign, 5 Uncertain significance, 1 Likely Benign).

**Submission history:** 17 submissions (2015–2026); classifications have differed over time.

**ClinGen expert panel:** Likely Benign — Hearing Loss VCEP (Usher syndrome). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `BP2`, `BS1_Supporting`.
*Considered but not met:* `PP3`.
Inheritance: Autosomal recessive inheritance.

> **Curation rationale (ClinGen, verbatim):** The c.1007G>A (p.Arg336His) variant in MYO7A is a missense variant predicted to cause a substitution of arginine by histidine at amino acid 336. The highest population minor allele frequency in gnomAD v4.1.0 is 0.00286 (2854/996858) in the non-Finnish European population, including 4 homozygous individuals, at least two of whom were beyond the average age of onset for MYO7A-related Usher syndrome. This frequency is higher than would be expected for an autosomal recessive condition based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (BS1_Supporting). This variant has been reported in individuals with nonsyndromic, mild-moderate hearing loss in whom a second variant was not detected (PMID: 23804846) as well as an individual with Usher syndrome but lacking a second variant (PMID: 16470552). A patient with Usher syndrome was homozygous for both p.Arg336His and a likely pathogenic/pathogenic variant (BP2; PMID: 33363762, ClinVar IDs: 551533). The REVEL computational prediction tool produced a score of 0.734, which is above the threshold necessary to apply PP3. However, after discussion the expert panel decided not to apply PP3 based upon case level and frequency data. In summary, this variant meets criteria to be classified as likely benign for both Usher syndrome and nonsyndromic hearing loss. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1_Supporting, BP2. (ClinGen Hearing Loss VCEP specifications version 2; 11.20.2024).
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50007 · approved 2024-11-20 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/63bd6cea-9e2a-4ad6-a8c4-5a0d13f28c7e).*
*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 |
| --- | --- | --- | --- | --- |
| Natera, Inc. | Likely benign | no assertion criteria provided | clinical testing | 2020-04-16 |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2020-08-10 |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-10-31 |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Likely benign | criteria provided, single submitter | clinical testing | 2015-08-11 |
| Illumina Laboratory Services, Illumina | Likely benign | criteria provided, single submitter | clinical testing | 2017-04-27 |
| Myriad Genetics, Inc. | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-11-04 |
| Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-11-03 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2022-11-09 |
| ClinGen Hearing Loss Variant Curation Expert Panel | Likely Benign | reviewed by expert panel | curation | 2024-11-20 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-02-04 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2025-09-01 |
| Centre for Mendelian Genomics, University Medical Centre Ljubljana | Uncertain significance | criteria provided, single submitter | clinical testing | 2019-09-24 |
| 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) | Likely benign | criteria provided, single submitter | clinical testing | 2016-03-02 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-22 |

## Associated conditions {#conditions}

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

## Same-residue context {#hotspot}

Residue **336** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [MYO7A p.Arg336fs](/variant/myo7a-p-arg336fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related MYO7A variant pages (same residue, condition, or type): [MYO7A p.Arg336Cys](/variant/myo7a-p-arg336cys), [MYO7A p.Arg336fs](/variant/myo7a-p-arg336fs), [MYO7A p.Arg336=](/variant/myo7a-p-arg336), [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 2026-10-14); 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 43134). 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.*