# NM_000260.4(MYO7A):c.3651C>T (p.His1217=)

https://sugi.bio/variant/myo7a-p-his1217

## Summary

**MYO7A p.His1217= (c.3651C>T)** is classified **Likely benign** in MYO7A (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-09-25). Ultra-rare (popmax 0.0553%, mid); Associated with Usher syndrome type 1B.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs776731918 · 6 submitters · 1 linked condition · ultra-rare (popmax 0.0553%, mid)

## For patients & families {#patients}

This is a change in the MYO7A gene that is classified as likely benign — not considered disease-causing, submitted by 6 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.His1217= |
| Coding change (HGVS c.) | c.3651C>T |
| MANE Select transcript | [NM_000260](https://www.ncbi.nlm.nih.gov/nuccore/NM_000260) |
| dbSNP | [rs776731918](https://www.ncbi.nlm.nih.gov/snp/rs776731918/) |
| Variant type | single nucleotide variant |
| Location | chr11:77190040-77190040 (GRCh38) |
| ClinVar | [VCV760829](https://www.ncbi.nlm.nih.gov/clinvar/variation/760829/) |

**All HGVS expressions:** `LRG_1420:g.66795C>T`, `LRG_1420t1:c.3651C>T`, `NC_000011.10:g.77190040C>T`, `NC_000011.9:g.76901085C>T`, `NG_009086.2:g.66795C>T`, `NM_000260.4:c.3651C>T`, `NM_001127180.2:c.3651C>T`, `NM_001369365.1:c.3618C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP -20, GERP -3.26 — fast-evolving / accelerated position
- CADD: **PHRED 0.208**. 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.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>G, Δ0.61 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0553%** (mid) · FAF95 0.0151% · FAF99 0.00962% · 3/5,422 in the highest group · 154/1,559,618 alleles overall — ultra-rare (popmax 0.0553%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0553% | 1,807 |
| European (non-Finnish) | 0.0119% | 8,412 |
| African / African-American | 0.00951% | 10,513 |
| Remaining individuals (not grpmax-eligible) | 0.00828% | 12,074 |
| Admixed American | 0.00383% | 26,081 |

*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 **1217** lies in the myth4 1 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.His1217= falls in the myth4 1 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 benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-09-25.

**Submitter consensus:** unanimous (6/6 Likely benign).

**Submission history:** 6 submissions (2020–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | Likely benign | no assertion criteria provided | clinical testing |  |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Likely benign | no assertion criteria provided | clinical testing |  |
| Natera, Inc. | Likely benign | no assertion criteria provided | clinical testing | 2020-01-28 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-09-25 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2023-04-01 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-08-19 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** not provided, Usher syndrome type 1B, not specified, AllHighlyPenetrant, Usher syndrome type IB, none provided.

## Similar variants {#similar}

Related MYO7A variant pages (same residue, condition, or type): [MYO7A p.His1217Gln](/variant/myo7a-p-his1217gln), [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 760829). 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.*