# NM_005068.3(SIM1):c.1598_1599dup (p.Val534fs)

https://sugi.bio/variant/sim1-p-val534fs

## Summary

**SIM1 p.Val534fs (c.1598_1599dup)** is classified **Uncertain significance** in SIM1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-05-15). Associated with SIM1-related disorder.

**At a glance:** Uncertain significance · review: No assertion criteria · 1 submitter · 1 linked condition

## For patients & families {#patients}

This is a change in the SIM1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to SIM1-related disorder.

*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 | [SIM1](https://sugi.bio/atlas/gene/SIM1/) |
| Protein change (HGVS p.) | p.Val534fs |
| Coding change (HGVS c.) | c.1598_1599dup |
| MANE Select transcript | [NM_005068](https://www.ncbi.nlm.nih.gov/nuccore/NM_005068) |
| Variant type | Microsatellite |
| Location | chr6:100391062-100391063 (GRCh38) |
| ClinVar | [VCV3345067](https://www.ncbi.nlm.nih.gov/clinvar/variation/3345067/) |

**All HGVS expressions:** `NC_000006.11:g.100838940AC[3]`, `NC_000006.12:g.100391064AC[3]`, `NG_008230.1:g.77610TG[3]`, `NG_008230.2:g.78855TG[3]`, `NM_001374769.1:c.1598_1599dup`, `NM_005068.3:c.1598_1599dup`

## 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 7.682, GERP 2.3, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.332, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (12 of 12)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no microsatellite variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.

*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}

**SIM1** population constraint: LOEUF 0.332, pLI 1, missense-Z 1.0526; ClinGen dosage — haploinsufficiency 0/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **534** lies in the single-minded c-terminal domain; the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 60.70, 31% of residues very-high.

## Clinical significance {#significance}

**Uncertain significance** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2024-05-15.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Uncertain significance | no assertion criteria provided | clinical testing | 2024-05-15 |

## Associated conditions {#conditions}

[SIM1-related disorder](https://sugi.bio/atlas/disease/sim1-related-disorder/).

**Reported phenotype names (ClinVar):** SIM1-related disorder, SIM1-related condition, SIM1-related disorders.

## Similar variants {#similar}

Related SIM1 variant pages (same residue, condition, or type): [SIM1 p.Leu265fs](/variant/sim1-p-leu265fs), [SIM1 p.Phe56fs](/variant/sim1-p-phe56fs), [SIM1 p.Arg374Trp](/variant/sim1-p-arg374trp), [SIM1 p.Ser199Cys](/variant/sim1-p-ser199cys), [SIM1 p.Gly480Ter](/variant/sim1-p-gly480ter), [SIM1 p.Thr481fs](/variant/sim1-p-thr481fs), [SIM1 c.-468+6T>A](/variant/sim1-c-minus-468-plus-6t-a), [SIM1 p.Ala484Ser](/variant/sim1-p-ala484ser).

### 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 3345067). 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.*