# NM_000260.4(MYO7A):c.5804T>C (p.Leu1935Pro)

https://sugi.bio/variant/myo7a-p-leu1935pro

## Summary

**MYO7A p.Leu1935Pro (c.5804T>C)** is classified **Likely pathogenic** in MYO7A (ClinVar, Expert panel, 7 submitters; last evaluated 2024-09-24). AlphaMissense: likely pathogenic (0.9824); Very rare (popmax 0.0022%, nfe); Associated with Usher syndrome.

**At a glance:** Likely pathogenic · review: Expert panel · rsID rs397516323 · 7 submitters · 4 linked conditions · AlphaMissense likely pathogenic · very rare (popmax 0.0022%, nfe)

## 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 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.Leu1935Pro |
| Coding change (HGVS c.) | c.5804T>C |
| MANE Select transcript | [NM_000260](https://www.ncbi.nlm.nih.gov/nuccore/NM_000260) |
| dbSNP | [rs397516323](https://www.ncbi.nlm.nih.gov/snp/rs397516323/) |
| Variant type | single nucleotide variant |
| Location | chr11:77207350-77207350 (GRCh38) |
| ClinVar | [VCV43298](https://www.ncbi.nlm.nih.gov/clinvar/variation/43298/) |

**All HGVS expressions:** `LRG_1420:g.84105T>C`, `LRG_1420t1:c.5804T>C`, `NC_000011.10:g.77207350T>C`, `NC_000011.9:g.76918395T>C`, `NG_009086.2:g.84105T>C`, `NM_000260.4(MYO7A):c.5804T>C`, `NM_000260.4:c.5804T>C`, `NM_001127180.2:c.5690T>C`, `NM_001369365.1:c.5657T>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9824) — concordant with the pathogenic call
- REVEL 0.961 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -17.617 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.911, GERP 1.71, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 28.7**. 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 **0.0022%** (nfe) · FAF95 0.00153% · FAF99 0.0013% · 26/1,179,460 in the highest group · 29/1,612,714 alleles overall — very rare (popmax 0.0022%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,220 |
| European (non-Finnish) (grpmax) | 0.0022% | 45,364 |
| African / African-American | 0.00133% | 74,912 |

Remaining individuals 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 **1935** lies in the ferm 2 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.Leu1935Pro falls in the ferm 2 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 (2 Likely pathogenic, 2 Likely Pathogenic, 2 Pathogenic, 1 Uncertain significance).

**Submission history:** 7 submissions (2010–2025); classifications have differed over time.

**ClinGen expert panel:** Likely Pathogenic — Hearing Loss VCEP (Usher syndrome). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `PM2_Supporting`, `PM3_Strong`, `PP3`, `PP4`.
*Considered but not met:* `BS1`, `BP4`, `BA1`.
Inheritance: Autosomal recessive inheritance.

> **Curation rationale (ClinGen, verbatim):** The c.5804T>C variant in MYO7A is a missense variant predicted to cause substitution of leucine by proline at amino acid 1935 (p.Leu1935Pro). The highest population minor allele frequency in gnomAD v4.1 is 0.00002204 (26/1179460 alleles) in the European (non-Finnish) population, which is lower than the ClinGen Hearing Loss VCEP threshold (≤0.00007) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.961, which is above the threshold of 0.7, evidence that correlates with impact to MYO7A function (PP3). This variant has been detected in 2 individuals with autosomal recessive Usher syndrome. Both were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and both of those were confirmed in trans by family testing (2 PM3 points, SCV001239772.1, SCV000059855.6, Blueprint Genetics, Laboratory for Molecular Medicine) (PM3_Strong). At least one patient with this variant displayed sensorineural hearing loss with retinitis pigmentosa, which is highly specific for autosomal recessive Usher syndrome (PP4, SCV000059855.6, Laboratory for Molecular Medicine). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM3_Strong, PM2_Supporting, PP3, PP4. (ClinGen Hearing Loss VCEP specifications version 2; 9/24/2024)
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50007 · approved 2024-09-24 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/1f484128-351e-49bd-a7a1-877c462ffac6).*
*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 |
| --- | --- | --- | --- | --- |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Likely pathogenic | no assertion criteria provided | clinical testing | 2010-08-16 |
| ClinGen Hearing Loss Variant Curation Expert Panel | Likely Pathogenic | reviewed by expert panel | curation | 2024-09-24 |
| Fulgent Genetics, Fulgent Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-05-09 |
| Counsyl | Uncertain significance | no assertion criteria provided | clinical testing | 2017-06-02 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-08-18 |
| Variantyx, Inc. | Likely Pathogenic | criteria provided, single submitter | clinical testing | 2025-08-14 |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2022-11-06 |

## 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/), [autosomal dominant nonsyndromic hearing loss 11](https://sugi.bio/atlas/disease/autosomal-dominant-nonsyndromic-hearing-loss-11/).

**Reported phenotype names (ClinVar):** Usher syndrome, Rare genetic deafness, Autosomal recessive nonsyndromic hearing loss 2, Usher syndrome type 1, not provided, Autosomal dominant nonsyndromic hearing loss 11, MYO7A-related disorder, MYO7A-related disorders, Usher Syndromes, Usher's syndrome.

## Similar variants {#similar}

Related MYO7A variant pages (same residue, condition, or type): [MYO7A p.Leu1935Met](/variant/myo7a-p-leu1935met), [MYO7A p.Leu1935=](/variant/myo7a-p-leu1935), [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 43298). 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.*