# NM_000143.4(FH):c.1247del (p.Val416fs)

https://sugi.bio/variant/fh-p-val416fs

## Summary

**FH p.Val416fs (c.1247del)** is classified **Pathogenic** in FH (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-10). No gnomAD frequency available for this variant; Associated with hereditary leiomyomatosis and renal cell cancer.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs2147913368 · 3 submitters · 2 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the FH gene that is considered disease-causing, submitted by 3 submitters, and is linked to hereditary leiomyomatosis and renal cell cancer.

*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 dominant |
| Age of onset (of this condition) | Adolescent, Adult, Elderly |
| Clinical trials | 9 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | FH is a diagnostic-grade gene on 18 Genomics England panels |

**Commonly reported features of Hereditary leiomyomatosis and renal cell cancer** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Abnormality of the musculature — Very frequent (99-80%)
- Multiple cutaneous leiomyomas — Very frequent (99-80%)
- Cutaneous leiomyoma — Very frequent (99-80%)
- Pruritus — Frequent (79-30%)
- Uterine leiomyoma — Occasional (29-5%)
- Cataract — Occasional (29-5%)
- Uterine leiomyosarcoma — Occasional (29-5%)
- Papillary renal cell carcinoma type 2 — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010096/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [FH](https://sugi.bio/atlas/gene/FH/) |
| Protein change (HGVS p.) | p.Val416fs |
| Coding change (HGVS c.) | c.1247del |
| MANE Select transcript | [NM_000143](https://www.ncbi.nlm.nih.gov/nuccore/NM_000143) |
| dbSNP | [rs2147913368](https://www.ncbi.nlm.nih.gov/snp/rs2147913368/) |
| Variant type | Deletion |
| Location | chr1:241500580-241500580 (GRCh38) |
| ClinVar | [VCV1455272](https://www.ncbi.nlm.nih.gov/clinvar/variation/1455272/) |

**All HGVS expressions:** `LRG_504:g.24175del`, `LRG_504t1:c.1247del`, `NC_000001.10:g.241663880del`, `NC_000001.11:g.241500580del`, `NG_012338.1:g.24175del`, `NM_000143.4:c.1247del`

## 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 -0.476, GERP -3.14 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene, supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 9 of 10**, so the transcript is predicted to undergo NMD.
- 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: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**FH** population constraint: LOEUF 0.599, pLI 0.26752, missense-Z 2.072; ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **hereditary leiomyomatosis and renal cell cancer** — Definitive (AD)

## Protein context {#protein}

Residue **416** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 92.92, 89% of residues very-high.

**8 experimental structure(s)** (PDB): [36AD](https://www.rcsb.org/structure/36AD), [3E04](https://www.rcsb.org/structure/3E04), [5D6B](https://www.rcsb.org/structure/5D6B), [5UPP](https://www.rcsb.org/structure/5UPP), [6EBT](https://www.rcsb.org/structure/6EBT), [6V8F](https://www.rcsb.org/structure/6V8F) — incl. mutant structure 6EBT.

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

*Describes the biological roles of FH (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:** FH's established molecular role includes fumarate hydratase activity.


### Pathways affected {#pathways}

FH participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Citric acid cycle (TCA cycle)](https://reactome.org/content/detail/R-HSA-71403) | curated |
| [Mitochondrial protein degradation](https://reactome.org/content/detail/R-HSA-9837999) | curated |

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

**Molecular function:** fumarate hydratase activity, histone binding.

**Biological process:** fumarate metabolic process, malate metabolic process, DNA damage response, positive regulation of double-strand break repair via nonhomologous end joining.

## Clinical significance {#significance}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-12-10.

**Submitter consensus:** unanimous (3/3 Pathogenic).

**Submission history:** 3 submissions (2021–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2021-10-25 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2022-01-13 |
| Myriad Genetics, Inc. | Pathogenic | criteria provided, single submitter | clinical testing | 2025-12-10 |

## Associated conditions {#conditions}

[hereditary leiomyomatosis and renal cell cancer](https://sugi.bio/atlas/disease/hereditary-leiomyomatosis-and-renal-cell-cancer/), [hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/).

**Reported phenotype names (ClinVar):** Hereditary leiomyomatosis and renal cell cancer, Hereditary cancer-predisposing syndrome, not provided, none provided, FH tumor predisposition syndrome, LEIOMYOMA, MULTIPLE CUTANEOUS, MULTIPLE CUTANEOUS AND UTERINE LEIOMYOMATA 1, WITH OR WITHOUT RENAL CELL CARCINOMA, Multiple cutaneous leiomyomas, Familial leiomyomatosis, Reed syndrome.

## Similar variants {#similar}

Related FH variant pages (same residue, condition, or type): [FH p.Val416Met](/variant/fh-p-val416met), [FH p.Val416=](/variant/fh-p-val416), [FH p.Val416Ala](/variant/fh-p-val416ala), [FH c.1058_1108+19del](/variant/fh-c-1058-1108-plus-19del), [FH c.1391-2del](/variant/fh-c-1391-minus-2del), [FH c.1392delG](/variant/fh-c-1392delg), [FH c.267+1_267+10del](/variant/fh-c-267-plus-1-267-plus-10del), [FH c.722_738+3del](/variant/fh-c-722-738-plus-3del).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 1455272). 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.*