# NM_000260.4(MYO7A):c.2904G>T (p.Glu968Asp)

https://sugi.bio/variant/myo7a-p-glu968asp

## Summary

**MYO7A p.Glu968Asp (c.2904G>T)** is classified **Likely pathogenic** in MYO7A (ClinVar, Expert panel, 10 submitters; last evaluated 2022-08-03). AlphaMissense: likely pathogenic (0.7644); Very rare (popmax 0.00644%, nfe); Associated with Usher syndrome type 1B.

**At a glance:** Likely pathogenic · review: Expert panel · rsID rs111033233 · 10 submitters · 5 linked conditions · AlphaMissense likely pathogenic · very rare (popmax 0.00644%, nfe)

## For patients & families {#patients}

This is a change in the MYO7A gene that is considered likely disease-causing, submitted by 10 submitters, and is linked to Usher syndrome type 1B.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 3 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0005436/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.Glu968Asp |
| Coding change (HGVS c.) | c.2904G>T |
| MANE Select transcript | [NM_000260](https://www.ncbi.nlm.nih.gov/nuccore/NM_000260) |
| dbSNP | [rs111033233](https://www.ncbi.nlm.nih.gov/snp/rs111033233/) |
| Variant type | single nucleotide variant |
| Location | chr11:77181589-77181589 (GRCh38) |
| ClinVar | [VCV43196](https://www.ncbi.nlm.nih.gov/clinvar/variation/43196/) |

**All HGVS expressions:** `LRG_1420:g.58344G>T`, `LRG_1420t1:c.2904G>T`, `NC_000011.10:g.77181589G>T`, `NC_000011.9:g.76892635G>T`, `NG_009086.2:g.58344G>T`, `NM_000260.4:c.2904G>T`, `NM_001127180.2:c.2904G>T`, `NM_001369365.1:c.2871G>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.7644) — concordant with the pathogenic call
- REVEL 0.563 (indeterminate)
- SaProt LLR -6.581 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate
- SpliceAI predicts **donor loss** (Δ 0.95) — consistent with the pathogenic call
- Conservation: phyloP 11.841, GERP 1.59, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 35.0**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.95**, acceptor gain **0.00**, donor gain **0.39**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.95**, acceptor gain **0.00**, donor gain **0.39**.
- Pangolin: Δ**0.83** (loss), gain 0.57 / loss 0.83. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00644%** (nfe) · FAF95 0.00528% · FAF99 0.00482% · 76/1,179,744 in the highest group · 78/1,612,662 alleles overall — very rare (popmax 0.00644%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00644% | 15,523 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,218 |

*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 **968** lies in a UniProt-annotated variant site (in ush1b).

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.


### 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 2022-08-03.

**Submitter consensus:** conflicting (7 Pathogenic, 3 Likely pathogenic).

**Submission history:** 10 submissions (2015–2025); classifications have differed over time.

**ClinGen expert panel:** Likely Pathogenic — Hearing Loss VCEP (Usher syndrome type 1B). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `PM2_Supporting`, `PM3_Strong`, `PP1`, `PP4`.
*Considered but not met:* `PP3`, `PM5`, `BP4`.
Inheritance: Autosomal recessive inheritance.

> **Curation rationale (ClinGen, verbatim):** The c.2904G>T variant in MYO7A is a missense variant predicted to cause substitution of glutamic acid by aspartic acid at amino acid 968. The highest population minor allele frequency in gnomAD v2.1.1 is 0.0000064 (3/126898 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 0.563, which is neither above nor below the thresholds predicting a damaging or benign impact on MYO7A function. At least one patient with this variant displayed Usher syndrome (PP4, PMID: 33089500). This variant has been detected in at least five individuals with Usher syndrome. Of those individuals, two were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and presumed to be in trans (c.631A>G (p.S211G) and c.3719G>A (p.D1240Q)) and three of those were confirmed in trans by family testing and all of whom had different variants on the other allele (c.224dup (p.D75fs), c.487G>C (p.G163R), c.1189G>A (p.A397T); 2.5 PM3 points, PMID: 25472526, 26969326, 33089500; ClinVar Variation ID: 43325, 43218, 553215) (PM3_Strong). The variant has been reported to segregate with Usher syndrome in three affected family members from one family (PP1; PMID:33089500). Another missense variant, c.2904G>C (p.E968D), in the same codon has been reported in a patient with Usher syndrome (PMID:27460420). However, this variant has not yet met the criteria to be classified as pathogenic or likely pathogenic by the ClinGen Hearing Loss VCEP (PM5 not met). 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: PM2_P, PP1, PP4, PM3_S (ClinGen Hearing Loss VCEP specifications version 2; 7/26/2022).
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50007 · approved 2022-08-03 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/19a2a2ac-617d-4a6b-ba5a-d3c5b8766be6).*
*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 |
| --- | --- | --- | --- | --- |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2015-09-22 |
| Genome-Nilou Lab | Pathogenic | criteria provided, single submitter | clinical testing | 2021-07-22 |
| Natera, Inc. | Pathogenic | criteria provided, single submitter | clinical testing | 2025-09-24 |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Pathogenic | criteria provided, single submitter | clinical testing | 2018-05-15 |
| ClinGen Hearing Loss Variant Curation Expert Panel | Likely pathogenic | reviewed by expert panel | curation | 2022-08-03 |
| Fulgent Genetics, Fulgent Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-04-11 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-09-03 |
| Genetics Research Center, University of Social Welfare and Rehabilitation Sciences | Likely pathogenic | criteria provided, single submitter | research | 2025-12-09 |
| Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-01-01 |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2022-06-21 |

## Associated conditions {#conditions}

[Usher syndrome type 1B](https://sugi.bio/atlas/disease/usher-syndrome-type-1b/), [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/), [inherited retinal dystrophy](https://sugi.bio/atlas/disease/inherited-retinal-dystrophy/).

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

## Same-residue context {#hotspot}

Residue **968** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [MYO7A p.Glu968=](/variant/myo7a-p-glu968). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related MYO7A variant pages (same residue, condition, or type): [MYO7A p.Glu968=](/variant/myo7a-p-glu968), [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), [MYO7A p.Gly2187Asp](/variant/myo7a-p-gly2187asp).

### 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 43196). 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.*