# NM_001353214.3(DYM):c.2043del (p.Lys681fs)

https://sugi.bio/variant/dym-p-lys681fs

## Summary

**DYM p.Lys681fs (c.2043del)** is classified **Pathogenic/Likely pathogenic** in DYM (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-06-04). Ultra-rare (popmax 0.0317%, amr); Associated with Dyggve-Melchior-Clausen disease.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs1471488189 · 5 submitters · 2 linked conditions · ultra-rare (popmax 0.0317%, amr)

## For patients & families {#patients}

This is a change in the DYM gene that is considered likely disease-causing, submitted by 5 submitters, and is linked to Dyggve-Melchior-Clausen disease.

*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) | Infancy |
| Diagnostic panels | DYM is a diagnostic-grade gene on 11 Genomics England panels |

**Commonly reported features of Dyggve-Melchior-Clausen disease** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Intellectual disability — Very frequent (99-80%)
- Failure to thrive — Very frequent (99-80%)
- Spondyloepimetaphyseal dysplasia — Very frequent (99-80%)
- Disproportionate short-trunk short stature — Very frequent (99-80%)
- Microcephaly — Frequent (79-30%)
- Coarse facial features — Frequent (79-30%)
- Short neck — Frequent (79-30%)
- Pectus carinatum — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006295/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DYM](https://sugi.bio/atlas/gene/DYM/) |
| Protein change (HGVS p.) | p.Lys681fs |
| Coding change (HGVS c.) | c.2043del |
| MANE Select transcript | [NM_001353214](https://www.ncbi.nlm.nih.gov/nuccore/NM_001353214) |
| dbSNP | [rs1471488189](https://www.ncbi.nlm.nih.gov/snp/rs1471488189/) |
| Variant type | Deletion |
| Location | chr18:49044187-49044187 (GRCh38) |
| ClinVar | [VCV3191](https://www.ncbi.nlm.nih.gov/clinvar/variation/3191/) |

**All HGVS expressions:** `NC_000018.10:g.49044189del`, `NC_000018.9:g.46570559del`, `NG_009239.2:g.421547del`, `NM_001353210.3:c.1875del`, `NM_001353211.3:c.1875del`, `NM_001353212.3:c.2040del`, `NM_001353213.3:c.2040del`, `NM_001353214.3:c.2043del`, `NM_001353215.3:c.1860del`, `NM_001353216.3:c.1695del`, `NM_001374428.1:c.2043del`, `NM_001374429.1:c.2037del`, `NM_001374430.1:c.*2del`, `NM_001374431.1:c.1929del`, `NM_001374432.1:c.1917del`, `NM_001374433.1:c.*2del`, `NM_001374434.1:c.1764del`, `NM_001374435.1:c.1761del`, `NM_001374436.1:c.1752del`, `NM_001374437.1:c.1695del`, `NM_001374438.1:c.1692del`, `NM_001374439.1:c.1689del`, `NM_001374440.1:c.1650del`, `NM_001374441.1:c.1473del`, `NM_001374442.1:c.1308del`, `NM_001374443.1:c.1305del`, `NM_001374444.1:c.1125del`, `NM_017653.6:c.1878del`, `NM_017653.6:c.1878delA`

## 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 11.153, GERP 2.33, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.081, pLI 7.9636e-21. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (18 of 18)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- CADD: **PHRED 28.4**. 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 deletion 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 **0.0317%** (amr) · FAF95 0.0207% · FAF99 0.0172% · 19/59,996 in the highest group · 23/1,614,070 alleles overall — ultra-rare (popmax 0.0317%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.0317% | 3,158 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,245 |
| European (non-Finnish) | 0.000169% | 590,023 |

*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}

**DYM** population constraint: LOEUF 1.081, pLI 7.9636e-21, missense-Z 0.92126; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, 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}


AlphaFold model confidence (whole protein): pLDDT 87.91, 72% of residues very-high.

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

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


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

**Molecular function:** enzyme binding.

**Biological process:** Golgi organization, bone development.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-06-04.

**Submitter consensus:** conflicting (4 Pathogenic, 1 Likely pathogenic).

**Submission history:** 5 submissions (2003–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Pathogenic | criteria provided, single submitter | clinical testing | 2018-07-10 |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2003-02-01 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-03-19 |
| First Genomix Gene Laboratory, Genetic Diagnostics Department | Pathogenic | criteria provided, single submitter | clinical testing | 2025-06-04 |
| 3billion | Pathogenic | criteria provided, single submitter | clinical testing | 2022-05-22 |

## Associated conditions {#conditions}

[Dyggve-Melchior-Clausen disease](https://sugi.bio/atlas/disease/dyggve-melchior-clausen-disease/), [Smith-McCort dysplasia 1](https://sugi.bio/atlas/disease/smith-mccort-dysplasia-1/).

**Reported phenotype names (ClinVar):** Dyggve-Melchior-Clausen syndrome, not provided, Smith-McCort dysplasia 1, Dyggve-Melchior-Clausen disease, DMC syndrome, Smith-McCort dwarfism, none provided.

## Similar variants {#similar}

Related DYM variant pages (same residue, condition, or type): [DYM p.Pro279fs](/variant/dym-p-pro279fs), [DYM p.Ser322fs](/variant/dym-p-ser322fs), [DYM c.1626-14_1626-4del](/variant/dym-c-1626-minus-14-1626-minus-4del), [DYM p.Asp408fs](/variant/dym-p-asp408fs), [DYM p.His393fs](/variant/dym-p-his393fs), [DYM p.Thr255fs](/variant/dym-p-thr255fs), [DYM c.1728+2T>C](/variant/dym-c-1728-plus-2t-c), [DYM c.947-2A>G](/variant/dym-c-947-minus-2a-g).

### 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 3191). 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.*