# NM_000117.3(EMD):c.19C>T (p.Leu7Phe)

https://sugi.bio/variant/emd-p-leu7phe

## Summary

**EMD p.Leu7Phe (c.19C>T)** is classified **Uncertain significance** in EMD (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-05-13). AlphaMissense: ambiguous (0.397); Very rare (popmax 0.00253%, amr); Associated with Cardiovascular phenotype.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs2067873080 · 3 submitters · 2 linked conditions · AlphaMissense ambiguous · very rare (popmax 0.00253%, amr)

## For patients & families {#patients}

This is a change in the EMD gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 3 submitters, and is linked to Cardiovascular phenotype.

*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 | [EMD](https://sugi.bio/atlas/gene/EMD/) |
| Protein change (HGVS p.) | p.Leu7Phe |
| Coding change (HGVS c.) | c.19C>T |
| MANE Select transcript | [NM_000117](https://www.ncbi.nlm.nih.gov/nuccore/NM_000117) |
| dbSNP | [rs2067873080](https://www.ncbi.nlm.nih.gov/snp/rs2067873080/) |
| Variant type | single nucleotide variant |
| Location | chrX:154379503-154379503 (GRCh38) |
| ClinVar | [VCV978372](https://www.ncbi.nlm.nih.gov/clinvar/variation/978372/) |

**All HGVS expressions:** `LRG_1340:g.136G>A`, `LRG_745:g.10068C>T`, `LRG_745t1:c.19C>T`, `NC_000023.10:g.153607863C>T`, `NC_000023.11:g.154379503C>T`, `NG_008677.1:g.10068C>T`, `NG_011506.2:g.136G>A`, `NM_000117.3:c.19C>T`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense and REVEL make no call here — the available evidence is described below.

- AlphaMissense **ambiguous** (0.397) — no call either way
- REVEL 0.344 (indeterminate)
- SaProt LLR -9.309 (tolerated)
- Conservation: phyloP 1.347, GERP 0.29, phastCons 0.833 — weakly conserved position
- CADD: **PHRED 18.85**. 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.*
- Regional missense constraint: **o/e 1.05** across the covering region of the MANE Select transcript (154,379,485–154,381,194), spanning 1,709 bp. Chi-square p 0.47. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00253%** (amr) · FAF95 3.8e-05% · FAF99 1.4e-05% · 1/39,568 in the highest group · 3/1,055,332 alleles overall — very rare (popmax 0.00253%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00253% | 39,568 |
| European (non-Finnish) | 0.000229% | 436,990 |

*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.*

## Protein context {#protein}

Residue **7** lies in the lem domain.

AlphaFold model confidence (whole protein): pLDDT 61.26, 20% of residues very-high.

**6 experimental structure(s)** (PDB): [1JEI](https://www.rcsb.org/structure/1JEI), [2ODC](https://www.rcsb.org/structure/2ODC), [2ODG](https://www.rcsb.org/structure/2ODG), [6GHD](https://www.rcsb.org/structure/6GHD), [6RPR](https://www.rcsb.org/structure/6RPR), [7NDY](https://www.rcsb.org/structure/7NDY) — incl. mutant structure 6RPR.

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

*Describes the biological roles of EMD (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:** EMD's established molecular role includes actin binding. p.Leu7Phe falls in the lem domain.


### Pathways affected {#pathways}

EMD participates in **9 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Depolymerization of the Nuclear Lamina](https://reactome.org/content/detail/R-HSA-4419969) | curated |
| [Initiation of Nuclear Envelope (NE) Reformation](https://reactome.org/content/detail/R-HSA-2995383) | curated |
| [Nuclear Envelope Breakdown](https://reactome.org/content/detail/R-HSA-2980766) | curated |
| [RAC1 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013149) | curated |
| [RAC2 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013404) | curated |
| [RAC3 GTPase cycle](https://reactome.org/content/detail/R-HSA-9013423) | curated |
| [RHOD GTPase cycle](https://reactome.org/content/detail/R-HSA-9013405) | curated |
| [RHOG GTPase cycle](https://reactome.org/content/detail/R-HSA-9013408) | curated |
| [Insertion of tail-anchored proteins into the endoplasmic reticulum membrane](https://reactome.org/content/detail/R-HSA-9609523) | electronic |

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

**Molecular function:** actin binding, cadherin binding, beta-tubulin binding.

**Biological process:** positive regulation of protein export from nucleus, negative regulation of fibroblast proliferation, regulation of canonical Wnt signaling pathway, cellular response to growth factor stimulus, nuclear membrane organization, negative regulation of canonical Wnt signaling pathway.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-05-13.

**Submitter consensus:** unanimous (3/3 Uncertain significance).

**Submission history:** 3 submissions (2025–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-04-08 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-08-10 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2026-05-13 |

## Associated conditions {#conditions}

[Cardiovascular phenotype](https://sugi.bio/atlas/disease/cardiovascular-phenotype/), [X-linked Emery-Dreifuss muscular dystrophy](https://sugi.bio/atlas/disease/x-linked-emery-dreifuss-muscular-dystrophy/).

**Reported phenotype names (ClinVar):** Cardiovascular phenotype, X-linked Emery-Dreifuss muscular dystrophy, Muscular dystrophy, tardive Emery-Dreifuss type, with contractures.

## Similar variants {#similar}

Related EMD variant pages (same residue, condition, or type): [EMD p.Leu7His](/variant/emd-p-leu7his), [EMD c.187+1G>A](/variant/emd-c-187-plus-1g-a), [EMD c.187+1G>T](/variant/emd-c-187-plus-1g-t), [EMD c.265+1G>A](/variant/emd-c-265-plus-1g-a), [EMD c.266-2A>G](/variant/emd-c-266-minus-2a-g), [EMD c.266-3A>G](/variant/emd-c-266-minus-3a-g), [EMD c.399+1G>T](/variant/emd-c-399-plus-1g-t), [EMD c.399+2T>C](/variant/emd-c-399-plus-2t-c).

### 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 978372). 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.*