# NM_145261.4(DNAJC19):c.307dup (p.Ile103fs)

https://sugi.bio/variant/dnajc19-p-ile103fs

## Summary

**DNAJC19 p.Ile103fs (c.307dup)** is classified **Uncertain significance** in DNAJC19 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-01). Associated with 3-methylglutaconic aciduria type 5.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition

## For patients & families {#patients}

This is a change in the DNAJC19 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to 3-methylglutaconic aciduria type 5.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Childhood, Infancy |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | DNAJC19 is a diagnostic-grade gene on 15 Genomics England panels |

**Commonly reported features of Dilated cardiomyopathy with ataxia** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Ataxia — Very frequent (99-80%)
- Growth delay — Very frequent (99-80%)
- Dilated cardiomyopathy — Very frequent (99-80%)
- Glutaric acidemia — Very frequent (99-80%)
- 3-Methylglutaconic aciduria — Very frequent (99-80%)
- Intrauterine growth retardation — Frequent (79-30%)
- Prolonged QT interval — Frequent (79-30%)
- Increased circulating lactate concentration — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0012964/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DNAJC19](https://sugi.bio/atlas/gene/DNAJC19/) |
| Protein change (HGVS p.) | p.Ile103fs |
| Coding change (HGVS c.) | c.307dup |
| MANE Select transcript | [NM_145261](https://www.ncbi.nlm.nih.gov/nuccore/NM_145261) |
| Variant type | Duplication |
| Location | chr3:180984683-180984684 (GRCh38) |
| ClinVar | [VCV4730301](https://www.ncbi.nlm.nih.gov/clinvar/variation/4730301/) |

**All HGVS expressions:** `LRG_743:g.10091dup`, `LRG_743t1:c.307dup`, `NC_000003.11:g.180702475dup`, `NC_000003.12:g.180984687dup`, `NG_022933.1:g.10091dup`, `NM_001190233.2:c.232dup`, `NM_145261.4:c.307dup`, `NR_033721.2:n.389dup`, `NR_033722.2:n.361dup`, `NR_033723.1:n.424dup`, `NR_046073.1:n.273dup`

## 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 11.225, GERP 1.96, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.547, pLI 7.1195e-05. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (6 of 6)** — 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 duplication 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}

**DNAJC19** population constraint: LOEUF 1.547, pLI 7.1195e-05, missense-Z 1.0653. *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):

- **3-methylglutaconic aciduria type 5** — Definitive (AR)

## Protein context {#protein}

Residue **103** lies in the j domain.

AlphaFold model confidence (whole protein): pLDDT 87.50, 56% of residues very-high.

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

*Describes the biological roles of DNAJC19 (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.*


### Pathways affected {#pathways}

DNAJC19 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Mitochondrial protein import](https://reactome.org/content/detail/R-HSA-1268020) | electronic |

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

**Biological process:** visual perception, genitalia development.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-11-01.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-11-01 |

## Associated conditions {#conditions}

[3-methylglutaconic aciduria type 5](https://sugi.bio/atlas/disease/3-methylglutaconic-aciduria-type-5/).

**Reported phenotype names (ClinVar):** 3-methylglutaconic aciduria type 5, CARDIOMYOPATHY, DILATED, WITH ATAXIA, MGA, TYPE V, 3 alpha methylglutaconic aciduria type V, MGA 5.

## Similar variants {#similar}

Related DNAJC19 variant pages (same residue, condition, or type): [DNAJC19 p.Tyr21Ter](/variant/dnajc19-p-tyr21ter), [DNAJC19 p.Lys57fs](/variant/dnajc19-p-lys57fs), [DNAJC19 c.280+2dup](/variant/dnajc19-c-280-plus-2dup), [DNAJC19 p.Ile99fs](/variant/dnajc19-p-ile99fs), [DNAJC19 c.281-15dup](/variant/dnajc19-c-281-minus-15dup), [DNAJC19 c.130-1G>C](/variant/dnajc19-c-130-minus-1g-c), [DNAJC19 c.280+1_280+5del](/variant/dnajc19-c-280-plus-1-280-plus-5del), [DNAJC19 c.4-1G>A](/variant/dnajc19-c-4-minus-1g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 4730301). 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.*