# NM_206933.4(USH2A):c.99_100insT (p.Arg34fs)

https://sugi.bio/variant/ush2a-p-arg34fs

## Summary

**USH2A p.Arg34fs (c.99_100insT)** is classified **Pathogenic/Likely pathogenic** in USH2A (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-03-11). Very rare (popmax 0.00669%, eas); Associated with Inborn genetic diseases.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs141672841 · 8 submitters · 3 linked conditions · very rare (popmax 0.00669%, eas)

## For patients & families {#patients}

This is a change in the USH2A gene that is considered likely disease-causing, submitted by 8 submitters, and is linked to Inborn genetic diseases.

*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.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [USH2A](https://sugi.bio/atlas/gene/USH2A/) |
| Protein change (HGVS p.) | p.Arg34fs |
| Coding change (HGVS c.) | c.99_100insT |
| MANE Select transcript | [NM_206933](https://www.ncbi.nlm.nih.gov/nuccore/NM_206933) |
| dbSNP | [rs141672841](https://www.ncbi.nlm.nih.gov/snp/rs141672841/) |
| Variant type | Insertion |
| Location | chr1:216422237-216422238 (GRCh38) |
| ClinVar | [VCV520636](https://www.ncbi.nlm.nih.gov/clinvar/variation/520636/) |

**All HGVS expressions:** `NC_000001.10:g.216595579_216595580insA`, `NC_000001.11:g.216422237_216422238insA`, `NG_009497.2:g.6211_6212insT`, `NM_007123.6:c.99_100insT`, `NM_206933.4:c.99_100insT`

## Computational & population evidence {#evidence}

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

- **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 3.68, GERP 0.812, phastCons 0.859 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.855, pLI 2.7327e-115. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 of 72**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 24.5**. 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: **not assessed** — the release is built from a substitutions-only source, so it holds no insertion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00669%** (eas) · FAF95 0.00177% · FAF99 0.000892% · 3/44,862 in the highest group · 3/1,613,080 alleles overall — very rare (popmax 0.00669%, eas).

*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}

**USH2A** population constraint: LOEUF 0.855, pLI 2.7327e-115, missense-Z 0.11215; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity Not yet evaluated/3. *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 2** — Definitive (AR)

## What this gene does {#gene-function}

*Describes the biological roles of USH2A (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:** USH2A's established molecular role includes collagen binding.


### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** collagen binding, myosin binding.

**Biological process:** sensory perception of sound, photoreceptor cell maintenance, maintenance of animal organ identity, sensory perception of light stimulus, inner ear receptor cell differentiation.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-03-11.

**Submitter consensus:** conflicting (7 Pathogenic, 1 Likely pathogenic).

**Submission history:** 8 submissions (2015–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Centre for Mendelian Genomics, University Medical Centre Ljubljana | Pathogenic | criteria provided, single submitter | clinical testing | 2019-03-31 |
| Ambry Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2015-03-19 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-01-21 |
| Genome-Nilou Lab | Pathogenic | criteria provided, single submitter | clinical testing | 2023-11-04 |
| Baylor Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2023-10-19 |
| SingHealth Duke-NUS Institute of Precision Medicine | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-02-05 |
| Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Pathogenic | criteria provided, single submitter | clinical testing | 2024-10-11 |
| Natera, Inc. | Pathogenic | criteria provided, single submitter | clinical testing | 2025-03-11 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/), [Usher syndrome type 2A](https://sugi.bio/atlas/disease/usher-syndrome-type-2a/), [retinitis pigmentosa 39](https://sugi.bio/atlas/disease/retinitis-pigmentosa-39/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, Usher syndrome type 2A, not provided, Retinitis pigmentosa 39, RETINAL DISEASE IN USHER SYNDROME TYPE IIA, MODIFIER OF, USHER SYNDROME, TYPE IIA, none provided.

## Same-residue context {#hotspot}

Residue **34** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [USH2A p.Arg34Ter](/variant/ush2a-p-arg34ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related USH2A variant pages (same residue, condition, or type): [USH2A p.Arg34Ter](/variant/ush2a-p-arg34ter), [USH2A p.Arg34Gln](/variant/ush2a-p-arg34gln), [USH2A p.Asn330Ter](/variant/ush2a-p-asn330ter), [USH2A p.Glu4051fs](/variant/ush2a-p-glu4051fs), [USH2A p.Tyr586Ter](/variant/ush2a-p-tyr586ter), [USH2A p.Ala1711fs](/variant/ush2a-p-ala1711fs), [USH2A p.Ala339fs](/variant/ush2a-p-ala339fs), [USH2A p.Leu6fs](/variant/ush2a-p-leu6fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 520636). 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.*