# NM_000260.4(MYO7A):c.1183C>T (p.Arg395Cys)

https://sugi.bio/variant/myo7a-p-arg395cys

## Summary

**MYO7A p.Arg395Cys (c.1183C>T)** is classified **Likely pathogenic** in MYO7A (ClinVar, Expert panel, 7 submitters; last evaluated 2024-09-24). AlphaMissense: likely pathogenic (0.8026); Very rare (popmax 0.00471%, sas); Associated with nonsyndromic genetic hearing loss.

**At a glance:** Likely pathogenic · review: Expert panel · rsID rs782279338 · 7 submitters · 6 linked conditions · AlphaMissense likely pathogenic · very rare (popmax 0.00471%, sas)

## For patients & families {#patients}

This is a change in the MYO7A gene that is considered likely disease-causing, submitted by 7 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.Arg395Cys |
| Coding change (HGVS c.) | c.1183C>T |
| MANE Select transcript | [NM_000260](https://www.ncbi.nlm.nih.gov/nuccore/NM_000260) |
| dbSNP | [rs782279338](https://www.ncbi.nlm.nih.gov/snp/rs782279338/) |
| Variant type | single nucleotide variant |
| Location | chr11:77160265-77160265 (GRCh38) |
| ClinVar | [VCV555138](https://www.ncbi.nlm.nih.gov/clinvar/variation/555138/) |

**All HGVS expressions:** `LRG_1420:g.37020C>T`, `LRG_1420t1:c.1183C>T`, `NC_000011.10:g.77160265C>T`, `NC_000011.9:g.76871311C>T`, `NG_009086.2:g.37020C>T`, `NM_000260.4(MYO7A):c.1183C>T`, `NM_000260.4:c.1183C>T`, `NM_001127180.2:c.1183C>T`, `NM_001369365.1:c.1150C>T`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.8026) — concordant with the pathogenic call
- REVEL 0.773 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -9.864 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL call this damaging; SaProt does not
- Conservation: phyloP 0.658, GERP -2.15, phastCons 0.098 — weakly conserved position
- CADD: **PHRED 29.1**. 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 2 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 **0.00471%** (sas) · FAF95 0.0016% · FAF99 0.000941% · 4/84,970 in the highest group · 18/1,568,648 alleles overall — very rare (popmax 0.00471%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.00471% | 21,243 |
| Admixed American | 0.00372% | 26,887 |
| Remaining individuals (not grpmax-eligible) | 0.00164% | 60,892 |
| European (non-Finnish) | 0.00095% | 105,231 |

*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 **395** 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.Arg395Cys 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 pathogenic** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2024-09-24.

**Submitter consensus:** conflicting (3 Likely pathogenic, 2 Pathogenic, 1 Likely Pathogenic, 1 Uncertain significance).

**Submission history:** 7 submissions (2017–2025); 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`, `PP3`, `PM3`.
*Considered but not met:* `PM2_Supporting`, `PP4`, `BS1`, `BP4`, `BA1`.
Inheritance: Autosomal recessive inheritance.

> **Curation rationale (ClinGen, verbatim):** The c.1183C>T variant in MYO7A is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 395. The highest population minor allele frequency in gnomAD v4.1 is 0.00008472 (2/23608 alleles) in the South Asian population. (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.773, which is above the threshold of 0.7, evidence that correlates with impact to MYO7A function (PP3). This variant has been detected in 6 individuals with nonsyndromic genetic hearing loss. Out of 3 of those individuals, 1 was compound heterozygous for the variant and a pathogenic or likely pathogenic variant for Usher syndrome and none of those were confirmed in trans (c.401T>A (p.Ile134Asn), 0 PM3 points, SCV: SCV001232108.5, Invitae). The other 2 were compound heterozygous for the variant and a variant of uncertain significance for nonsyndromic genetic hearing loss, 1 of them was confirmed in trans by family testing (0.25 PM3 points, c.1496T>C (p.Ile499Thr); c.1496T>C(p.Ile499Thr), PMIDs: 34416374, 34979615). 3 individuals were homozygous for the variant (1 PM3 point, PMIDs: 23770805, 27573290, ClinVar SCV: SCV001232108.5, Invitae) (PM3). The variant has been reported to segregate with nonsyndromic genetic hearing loss in 8 affected family members from 3 families (PP1_Strong; PMIDs: 23770805, 27573290, 34979615). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive nonsyndromic genetic hearing loss based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PP1_Strong, PM3, PP3. (ClinGen Hearing Loss VCEP specifications version 2; 7/23/2024)
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50007 · approved 2024-09-24 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/55512a59-1ed0-41e4-80d2-be897c90cfe6).*
*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 |
| --- | --- | --- | --- | --- |
| University of Washington Center for Mendelian Genomics, University of Washington | Likely pathogenic | no assertion criteria provided | research |  |
| ClinGen Hearing Loss Variant Curation Expert Panel | Likely Pathogenic | reviewed by expert panel | curation | 2024-09-24 |
| Counsyl | Uncertain significance | no assertion criteria provided | clinical testing | 2017-11-17 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-03-02 |
| Natera, Inc. | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-05-30 |
| Fulgent Genetics, Fulgent Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-03-28 |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-09-24 |

## 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/), [hearing loss, autosomal recessive](https://sugi.bio/atlas/disease/hearing-loss-autosomal-recessive/), [Usher syndrome type 1B](https://sugi.bio/atlas/disease/usher-syndrome-type-1b/).

**Reported phenotype names (ClinVar):** Nonsyndromic genetic hearing loss, Autosomal recessive nonsyndromic hearing loss 2, Usher syndrome type 1, not provided, Hearing loss, autosomal recessive, Usher syndrome type 1B, Autosomal dominant nonsyndromic hearing loss 11, MYO7A-related disorder, NEUROSENSORY NONSYNDROMIC RECESSIVE DEAFNESS 2, DEAFNESS, AUTOSOMAL RECESSIVE 2.

## Same-residue context {#hotspot}

Residue **395** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [MYO7A p.Arg395His](/variant/myo7a-p-arg395his). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related MYO7A variant pages (same residue, condition, or type): [MYO7A p.Arg395His](/variant/myo7a-p-arg395his), [MYO7A p.Arg395=](/variant/myo7a-p-arg395), [MYO7A p.Ala1288Pro](/variant/myo7a-p-ala1288pro), [MYO7A p.Arg1168Gln](/variant/myo7a-p-arg1168gln), [MYO7A p.Arg1873Gln](/variant/myo7a-p-arg1873gln), [MYO7A p.Arg668Cys](/variant/myo7a-p-arg668cys), [MYO7A p.Arg853His](/variant/myo7a-p-arg853his), [MYO7A p.Glu968Asp](/variant/myo7a-p-glu968asp).

### 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 555138). 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.*