MYO7A p.Leu328Pro
c.983T>C · rs1281366817 · VCV1308583
ClinGen expert panel — Hearing Loss VCEP
Uncertain Significance for Usher syndrome type 1B. Applied ACMG criteria (verbatim):
PM3_Supporting PM2_Supporting PP3 PP4
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).
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.9871 | likely pathogenic |
|---|---|---|
| REVEL | 0.877 | moderately pathogenic-leaning |
| SaProt | LLR -17.23 | damaging |
| ⇒ AlphaMissense, REVEL and SaProt all call this damaging. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 7.9 | GERP 1.8, phastCons 1 |
| Regional constraint | o/e 0.95 | unconstrained · MANE · 84 kb · p 0.0065 · regional, not allelic |
| Overall | ||
| CADD | 26.3 | PHRED · no single calibrated threshold — expert panels disagree |
ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.
Variant & gene context
- Gene
- MYO7A
- Protein
- p.Leu328Pro
- Coding
- c.983T>C
- MANE Select
- NM_000260
- dbSNP
- rs1281366817
- Type
- single nucleotide variant
- Location
- chr11:77158410 (GRCh38)
- Gene constraint
- LOEUF 0.995 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 77.73 · 1 PDB
- Residue 328
- the myosin motor domain
Similar variants
- MYO7A p.Leu328= Conflicting classifications of pathogenicity ★ same residue
- MYO7A p.Ala1288Pro Likely pathogenic ★★★ same condition
- MYO7A p.Arg1168Gln Pathogenic ★★★ ⚠ same condition
- MYO7A p.Arg1873Gln Pathogenic ★★★ ⚠ same condition
- MYO7A p.Arg395Cys Likely pathogenic ★★★ ⚠ same condition
- MYO7A p.Arg668Cys Pathogenic ★★★ same condition
- MYO7A p.Arg853His Likely pathogenic ★★★ same condition
- MYO7A p.Glu968Asp Likely pathogenic ★★★ ⚠ same condition
Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →
Cite Sugi Variant
Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/myo7a-p-leu328pro (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown