# NM_000260.4(MYO7A):c.983T>C (p.Leu328Pro)

https://sugi.bio/variant/myo7a-p-leu328pro

## Summary

**MYO7A p.Leu328Pro (c.983T>C)** is classified **Uncertain significance** in MYO7A (ClinVar, Expert panel, 3 submitters; last evaluated 2024-12-18). AlphaMissense: likely pathogenic (0.9871); Absent from gnomAD v4.1; Associated with Usher syndrome type 1B.

**At a glance:** Uncertain significance · review: Expert panel · rsID rs1281366817 · 3 submitters · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## 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 3 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.Leu328Pro |
| Coding change (HGVS c.) | c.983T>C |
| MANE Select transcript | [NM_000260](https://www.ncbi.nlm.nih.gov/nuccore/NM_000260) |
| dbSNP | [rs1281366817](https://www.ncbi.nlm.nih.gov/snp/rs1281366817/) |
| Variant type | single nucleotide variant |
| Location | chr11:77158410-77158410 (GRCh38) |
| ClinVar | [VCV1308583](https://www.ncbi.nlm.nih.gov/clinvar/variation/1308583/) |

**All HGVS expressions:** `LRG_1420:g.35165T>C`, `LRG_1420t1:c.983T>C`, `NC_000011.10:g.77158410T>C`, `NC_000011.9:g.76869456T>C`, `NG_009086.2:g.35165T>C`, `NM_000260.4:c.983T>C`, `NM_001127180.2:c.983T>C`, `NM_001369365.1:c.950T>C`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.9871)
- REVEL 0.877 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -17.228 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.906, GERP 1.76, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 26.3**. 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 **328** 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.Leu328Pro 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 2024-12-18.

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

**Submission history:** 3 submissions (2019–2024); classifications have differed over time.

**ClinGen expert panel:** Uncertain Significance — Hearing Loss VCEP (Usher syndrome type 1B). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `PM3_Supporting`, `PM2_Supporting`, `PP3`, `PP4`.
*Considered but not met:* `BS1`, `BA1`.
Inheritance: Autosomal recessive inheritance.

> **Curation rationale (ClinGen, verbatim):** The variant NM_000260.4:c.983T>C in MYO7A is a missense variant predicted to cause substitution of leucine by proline at amino acid 328 (p.Leu328Pro). The variant is absent from gnomAD v4.1.0 (PM2_Supporting). The variant p.Leu328Pro variant was identified by multigene panel testing in a three year old male proband with congenital bilateral profound sensorineural hearing loss and pigmentary retinopathy, delayed motor milestones, blonde fundus, and a diagnosis of Usher Syndrome 1B (PP4, PMID: 32281467). The proband also harbored a likely pathogenic variant NM_000260(MYO7A):c.471-2A>C, however the phase of the variants was not confirmed (0.5 PM3 points, PM3_Supporting; PMID: 32281467). The computational predictor REVEL gives a score of 0.877, which is above the threshold necessary to apply PP3 (PP3). There is a ClinVar entry for this variant (Variation ID: 1308583, one star review status), with one submitter classifying the variant as uncertain significance. 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: PM2_Supporting, PP3, PP4, PM3_Supporting (ClinGen Hearing Loss VCEP specifications version 2; 12/18/2024).
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50007 · approved 2024-12-18 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/7cdf2c5e-e1ab-4248-b4a4-ff015e04deb2).*
*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 | Uncertain significance | criteria provided, single submitter | clinical testing | 2019-04-17 |
| ClinGen Hearing Loss Variant Curation Expert Panel | Uncertain Significance | reviewed by expert panel | curation | 2024-12-18 |
| Blueprint Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-12-14 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Usher syndrome type 1B, not provided, MYO7A-related disorder, Usher syndrome type IB, MYO7A-related disorders, none provided.

## Same-residue context {#hotspot}

Residue **328** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [MYO7A p.Leu328fs](/variant/myo7a-p-leu328fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related MYO7A variant pages (same residue, condition, or type): [MYO7A p.Leu328=](/variant/myo7a-p-leu328), [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.Glu968Asp](/variant/myo7a-p-glu968asp).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 1308583). 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.*