# NM_020549.5(CHAT):c.2107TCT[1] (p.Ser705del)

https://sugi.bio/variant/chat-p-ser705del

## Summary

**CHAT p.Ser705del (c.2107TCT[1])** is classified **Conflicting classifications of pathogenicity** in CHAT (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-06-20). Very rare (popmax 0.00666%, amr); Associated with congenital myasthenic syndrome 6.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs750942168 · 3 submitters · 1 linked condition · very rare (popmax 0.00666%, amr)

## For patients & families {#patients}

This is a change in the CHAT gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 3 submitters, and is linked to congenital myasthenic syndrome 6.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0009689/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CHAT](https://sugi.bio/atlas/gene/CHAT/) |
| Protein change (HGVS p.) | p.Ser705del |
| Coding change (HGVS c.) | c.2107TCT[1] |
| MANE Select transcript | [NM_020549](https://www.ncbi.nlm.nih.gov/nuccore/NM_020549) |
| dbSNP | [rs750942168](https://www.ncbi.nlm.nih.gov/snp/rs750942168/) |
| Variant type | Microsatellite |
| Location | chr10:49664904-49664906 (GRCh38) |
| ClinVar | [VCV648773](https://www.ncbi.nlm.nih.gov/clinvar/variation/648773/) |

**All HGVS expressions:** `NC_000010.10:g.50872952TCT[1]`, `NC_000010.11:g.49664906TCT[1]`, `NG_011797.1:g.60812TCT[1]`, `NM_001142929.2:c.1753TCT[1]`, `NM_001142933.2:c.1861TCT[1]`, `NM_001142934.2:c.1753TCT[1]`, `NM_020549.4:c.2110_2112delTCT`, `NM_020549.5:c.2107TCT[1]`, `NM_020549.5:c.2110_2112del`, `NM_020984.4:c.1753TCT[1]`, `NM_020985.4:c.1753TCT[1]`, `NM_020986.4:c.1753TCT[1]`

## 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 11.173, GERP 2.2, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **in-frame indel**.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no microsatellite 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 **0.00666%** (amr) · FAF95 0.00225% · FAF99 0.00135% · 4/60,032 in the highest group · 11/1,614,170 alleles overall — very rare (popmax 0.00666%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00666% | 15,008 |
| South Asian | 0.0011% | 91,078 |
| European (non-Finnish) | 0.000508% | 196,672 |

*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}

**CHAT** population constraint: LOEUF 0.973, pLI 9.9145e-17, missense-Z 0.67235; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity Not yet evaluated/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):

- **congenital myasthenic syndrome 6** — Definitive (AR)

## Protein context {#protein}

Residue **705** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 84.73, 75% of residues very-high.

**8 experimental structure(s)** (PDB): [2FY2](https://www.rcsb.org/structure/2FY2), [2FY3](https://www.rcsb.org/structure/2FY3), [2FY4](https://www.rcsb.org/structure/2FY4), [2FY5](https://www.rcsb.org/structure/2FY5), [7AMD](https://www.rcsb.org/structure/7AMD), [9F84](https://www.rcsb.org/structure/9F84).

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

*Describes the biological roles of CHAT (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}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Synthesis of PC](https://reactome.org/content/detail/R-HSA-1483191) | curated |
| [Acetylcholine Neurotransmitter Release Cycle](https://reactome.org/content/detail/R-HSA-264642) | other |

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-06-20.

**Submitter consensus:** conflicting (2 Likely pathogenic, 1 Uncertain significance).

**Submission history:** 3 submissions (2024–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| 3billion | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-03-13 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-04-30 |
| GeneDx | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-06-20 |

## Associated conditions {#conditions}

[congenital myasthenic syndrome 6](https://sugi.bio/atlas/disease/congenital-myasthenic-syndrome-6/).

**Reported phenotype names (ClinVar):** Familial infantile myasthenia, not provided, none provided, Congenital myasthenic syndrome type 6, MYASTHENIC SYNDROME, PRESYNAPTIC, CONGENITAL, ASSOCIATED WITH EPISODIC APNEA, MYASTHENIC SYNDROME, CONGENITAL, 6, PRESYNAPTIC.

## Similar variants {#similar}

Related CHAT variant pages (same residue, condition, or type): [CHAT c.1382+2_1382+3del](/variant/chat-c-1382-plus-2-1382-plus-3del), [CHAT p.Asn569del](/variant/chat-p-asn569del), [CHAT p.Ser279del](/variant/chat-p-ser279del), [CHAT c.1282-14_1282-13del](/variant/chat-c-1282-minus-14-1282-minus-13del), [CHAT c.1777-17_1777-16del](/variant/chat-c-1777-minus-17-1777-minus-16del), [CHAT c.286+11GGGCT[4]](/variant/chat-c-286-plus-11gggct-4), [CHAT c.286+9_286+11del](/variant/chat-c-286-plus-9-286-plus-11del), [CHAT c.1282-2A>T](/variant/chat-c-1282-minus-2a-t).

### 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 648773). 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.*