# NM_000260.4(MYO7A):c.1997G>A (p.Arg666Gln)

https://sugi.bio/variant/myo7a-p-arg666gln

## Summary

**MYO7A p.Arg666Gln (c.1997G>A)** is classified **Uncertain significance** in MYO7A (ClinVar, Expert panel, 8 submitters; last evaluated 2025-03-12). AlphaMissense: ambiguous (0.4053); Ultra-rare (popmax 0.0187%, afr); Associated with Usher syndrome.

**At a glance:** Uncertain significance · review: Expert panel · rsID rs782396605 · 8 submitters · 4 linked conditions · AlphaMissense ambiguous · ultra-rare (popmax 0.0187%, afr)

## For patients & families {#patients}

This is a change in the MYO7A gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 8 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.Arg666Gln |
| Coding change (HGVS c.) | c.1997G>A |
| MANE Select transcript | [NM_000260](https://www.ncbi.nlm.nih.gov/nuccore/NM_000260) |
| dbSNP | [rs782396605](https://www.ncbi.nlm.nih.gov/snp/rs782396605/) |
| Variant type | single nucleotide variant |
| Location | chr11:77174817-77174817 (GRCh38) |
| ClinVar | [VCV556881](https://www.ncbi.nlm.nih.gov/clinvar/variation/556881/) |

**All HGVS expressions:** `LRG_1420:g.51572G>A`, `LRG_1420t1:c.1997G>A`, `NC_000011.10:g.77174817G>A`, `NC_000011.9:g.76885863G>A`, `NG_009086.2:g.51572G>A`, `NM_000260.4(MYO7A):c.1997G>A`, `NM_000260.4:c.1997G>A`, `NM_001127180.2:c.1997G>A`, `NM_001369365.1:c.1964G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **ambiguous** (0.4053) — no call either way
- REVEL 0.841 (moderately pathogenic-leaning)
- SaProt LLR -11.663 (damaging)
- → **In-silico consensus:** REVEL and SaProt both call this damaging; AlphaMissense is indeterminate
- Conservation: phyloP 5.875, GERP -0.414, phastCons 1 — highly conserved
- CADD: **PHRED 29.3**. 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: **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 34 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 **0.0187%** (afr) · FAF95 0.0112% · FAF99 0.00903% · 14/75,048 in the highest group · 26/1,613,040 alleles overall — ultra-rare (popmax 0.0187%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0187% | 5,361 |
| Remaining individuals (not grpmax-eligible) | 0.00801% | 12,491 |
| Admixed American | 0.00167% | 59,944 |
| European (non-Finnish) | 0.000509% | 196,616 |

*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 **666** 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.Arg666Gln 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}

**Uncertain significance** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2025-03-12.

**Submitter consensus:** conflicting (7 Uncertain significance, 1 Uncertain Significance).

**Submission history:** 8 submissions (2018–2025); classifications have been stable.

**ClinGen expert panel:** Uncertain Significance — Hearing Loss VCEP (Usher syndrome). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `PP3`.
*Considered but not met:* `PM2_Supporting`, `BS1_Supporting`.
Inheritance: Autosomal recessive inheritance.

> **Curation rationale (ClinGen, verbatim):** The c.1997G>A variant in MYO7A is a missense variant predicted to cause substitution of arginine by glycine at amino acid 666. The highest population minor allele frequency in gnomAD v4.1 is 0.0001865 (14/75048 alleles) in the African/African-American population (PM2_Supporting and BS1_Supporting are not met). The computational predictor REVEL gives a score of 0.841, which is above the threshold of 0.7, evidence that correlates with impact to MYO7A function (PP3). This variant has been observed in one proband with Usher syndrome, four probands with hearing loss, and two probands with retinal disease. However, they all harbored another variant of uncertain significance c.3527G>A (p.Ser1176Asn) with phase unknown, and two who were found to have an alternate molecular basis for disease (PM3_Supporting not met; ClinVar ID: 196099; PMIDs: 27460420, 31479088, 33297549, 27344577, LabCorp Genetics (formerly Invitae) internal data ClinVar SCV001498602.2, GeneDx internal data). In summary, this variant has been classified as a variant of uncertain significance for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PP3 (ClinGen Hearing Loss VCEP specifications version 2; 3/12/2025).
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50007 · approved 2025-03-12 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/4923dcaa-6018-41a1-b68f-39af89d9e3cf).*
*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. | Uncertain significance | no assertion criteria provided | clinical testing | 2020-01-16 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-09-13 |
| Mendelics | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-04-21 |
| Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-03-25 |
| Counsyl | Uncertain significance | no assertion criteria provided | clinical testing | 2018-02-28 |
| ClinGen Hearing Loss Variant Curation Expert Panel | Uncertain Significance | reviewed by expert panel | curation | 2025-03-12 |
| Dasa | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-10-07 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-03-02 |

## Associated conditions {#conditions}

[Usher syndrome](https://sugi.bio/atlas/disease/usher-syndrome/), [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):** Usher syndrome, Autosomal recessive nonsyndromic hearing loss 2, Usher syndrome type 1, not provided, Usher syndrome type 1B, none provided, Usher syndrome type IB, RETINITIS PIGMENTOSA AND CONGENITAL DEAFNESS, DEAFNESS, AUTOSOMAL RECESSIVE 2, NEUROSENSORY NONSYNDROMIC RECESSIVE DEAFNESS 2.

## Same-residue context {#hotspot}

Residue **666** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [MYO7A p.Arg666Ter](/variant/myo7a-p-arg666ter), [MYO7A p.Arg666Pro](/variant/myo7a-p-arg666pro). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related MYO7A variant pages (same residue, condition, or type): [MYO7A p.Arg666Ter](/variant/myo7a-p-arg666ter), [MYO7A p.Arg666Pro](/variant/myo7a-p-arg666pro), [MYO7A p.Arg666=](/variant/myo7a-p-arg666), [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 556881). 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.*