# NM_213599.3(ANO5):c.1689T>C (p.Phe563=)

https://sugi.bio/variant/ano5-p-phe563

## Summary

**ANO5 p.Phe563= (c.1689T>C)** is classified **Conflicting classifications of pathogenicity** in ANO5 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-06-10). Very rare (popmax 0.00144%, nfe); Associated with autosomal recessive limb-girdle muscular dystrophy type 2L.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs527322470 · 4 submitters · 2 linked conditions · very rare (popmax 0.00144%, nfe)

## For patients & families {#patients}

This is a change in the ANO5 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 4 submitters, and is linked to autosomal recessive limb-girdle muscular dystrophy type 2L.

*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) | Adolescent, Adult, Childhood |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | ANO5 is a diagnostic-grade gene on 7 Genomics England panels |

**Commonly reported features of Anoctamin-5-related limb-girdle muscular dystrophy R12** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Myalgia — Very frequent (99-80%)
- Limb-girdle muscular dystrophy — Very frequent (99-80%)
- Proximal muscle weakness in lower limbs — Very frequent (99-80%)
- Distal lower limb muscle weakness — Very frequent (99-80%)
- Abnormality of the calf musculature — Frequent (79-30%)
- Genu recurvatum — Frequent (79-30%)
- Elevated circulating creatine kinase concentration — Frequent (79-30%)
- EMG: neuropathic changes — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0012536/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ANO5](https://sugi.bio/atlas/gene/ANO5/) |
| Protein change (HGVS p.) | p.Phe563= |
| Coding change (HGVS c.) | c.1689T>C |
| MANE Select transcript | [NM_213599](https://www.ncbi.nlm.nih.gov/nuccore/NM_213599) |
| dbSNP | [rs527322470](https://www.ncbi.nlm.nih.gov/snp/rs527322470/) |
| Variant type | single nucleotide variant |
| Location | chr11:22262187-22262187 (GRCh38) |
| ClinVar | [VCV290518](https://www.ncbi.nlm.nih.gov/clinvar/variation/290518/) |

**All HGVS expressions:** `LRG_868:g.74012T>C`, `NC_000011.10:g.22262187T>C`, `NC_000011.9:g.22283733T>C`, `NG_015844.1:g.74012T>C`, `NM_001142649.2:c.1686T>C`, `NM_213599.3:c.1689T>C`

## 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 1.434, GERP -1.33, phastCons 1 — weakly conserved position
- CADD: **PHRED 16.26**. 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: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for ANO5 (1,293 scored positions, the nearest 2 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **0.00144%** (nfe) · FAF95 0.000878% · FAF99 0.000717% · 17/1,179,960 in the highest group · 17/1,613,884 alleles overall — very rare (popmax 0.00144%, nfe).

*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}

**ANO5** population constraint: LOEUF 1.034, pLI 2.1745e-26, missense-Z 0.71114. *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):

- **autosomal recessive limb-girdle muscular dystrophy** — Definitive (AR)
- **gnathodiaphyseal dysplasia** — Definitive (AD)

## Protein context {#protein}

Residue **563** lies in a UniProt-annotated variant site (in lgmdr12); a UniProt-annotated variant site (in lgmdr12; uncertain significance).

AlphaFold model confidence (whole protein): pLDDT 82.22, 39% of residues very-high.

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

*Describes the biological roles of ANO5 (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:** ANO5's established molecular role includes intracellularly calcium-gated chloride channel activity. In Reactome, ANO5 is annotated in disease pathway(s) including **Induction of Cell-Cell Fusion**.

**Disease mechanism (Reactome):** ANO5 loss or alteration is curated in [Induction of Cell-Cell Fusion](https://reactome.org/content/detail/R-HSA-9733458).

### Pathways affected {#pathways}

ANO5 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Induction of Cell-Cell Fusion](https://reactome.org/content/detail/R-HSA-9733458) | curated |
| [Regulation of clotting cascade](https://reactome.org/content/detail/R-HSA-9769739) | curated |
| [Stimuli-sensing channels](https://reactome.org/content/detail/R-HSA-2672351) | curated |

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

**Molecular function:** intracellularly calcium-gated chloride channel activity.

**Biological process:** plasma membrane repair, chloride transmembrane transport.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-06-10.

**Submitter consensus:** conflicting (3 Likely benign, 1 Uncertain significance).

**Submission history:** 4 submissions (2016–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | Likely benign | no assertion criteria provided | clinical testing |  |
| Eurofins Ntd Llc (ga) | Uncertain significance | criteria provided, single submitter | clinical testing | 2016-09-23 |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Likely benign | no assertion criteria provided | clinical testing |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-06-10 |

## Associated conditions {#conditions}

[autosomal recessive limb-girdle muscular dystrophy type 2L](https://sugi.bio/atlas/disease/autosomal-recessive-limb-girdle-muscular-dystrophy-type-2l/), [gnathodiaphyseal dysplasia](https://sugi.bio/atlas/disease/gnathodiaphyseal-dysplasia/).

**Reported phenotype names (ClinVar):** Autosomal recessive limb-girdle muscular dystrophy type 2L, not provided, Gnathodiaphyseal dysplasia, Limb-girdle muscular dystrophy, type 2L, Limb-Girdle Muscular Dystrophy R12 Anoctamin-5-Related (LGMD-R12), MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 12, GNATHODIAPHYSEAL SCLEROSIS, OSTEOGENESIS IMPERFECTA WITH UNUSUAL SKELETAL LESIONS, none provided.

## Similar variants {#similar}

Related ANO5 variant pages (same residue, condition, or type): [ANO5 c.1898+1G>A](/variant/ano5-c-1898-plus-1g-a), [ANO5 c.41-1G>A](/variant/ano5-c-41-minus-1g-a), [ANO5 p.Ala432Gly](/variant/ano5-p-ala432gly), [ANO5 p.Arg484Cys](/variant/ano5-p-arg484cys), [ANO5 p.Arg50Ter](/variant/ano5-p-arg50ter), [ANO5 p.Arg58Trp](/variant/ano5-p-arg58trp), [ANO5 p.Arg758Cys](/variant/ano5-p-arg758cys), [ANO5 p.Asp81Gly](/variant/ano5-p-asp81gly).

### 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 290518). 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.*