NM_020549.5(CHAT):c.1721C>T (p.Thr574Ile) AND Familial infantile myasthenia

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Mar 10, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001232267.7

Allele description [Variation Report for NM_020549.5(CHAT):c.1721C>T (p.Thr574Ile)]

NM_020549.5(CHAT):c.1721C>T (p.Thr574Ile)

Gene:

CHAT:choline O-acetyltransferase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

10q11.23

Genomic location:

Preferred name:

NM_020549.5(CHAT):c.1721C>T (p.Thr574Ile)

HGVS:

NC_000010.11:g.49655181C>T
NG_011797.1:g.51087C>T
NM_001142929.2:c.1367C>T
NM_001142933.2:c.1475C>T
NM_001142934.2:c.1367C>T
NM_020549.5:c.1721C>TMANE SELECT
NM_020984.4:c.1367C>T
NM_020985.4:c.1367C>T
NM_020986.4:c.1367C>T
NP_001136401.2:p.Thr456Ile
NP_001136405.2:p.Thr492Ile
NP_001136406.2:p.Thr456Ile
NP_065574.4:p.Thr574Ile
NP_066264.4:p.Thr456Ile
NP_066265.4:p.Thr456Ile
NP_066266.4:p.Thr456Ile
NC_000010.10:g.50863227C>T
NM_020549.4:c.1721C>T

Protein change:

T456I

Links:

dbSNP: rs1839995781

NCBI 1000 Genomes Browser:

rs1839995781

Molecular consequence:

NM_001142929.2:c.1367C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001142933.2:c.1475C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001142934.2:c.1367C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_020549.5:c.1721C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_020984.4:c.1367C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_020985.4:c.1367C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_020986.4:c.1367C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial infantile myasthenia (CMS6)
Synonyms:: Congenital myasthenic syndrome with episodic apnea; Myasthenic syndrome congenital associated with episodic apnea; Myasthenic syndrome, presynaptic, congenital, associated with episodic apnea; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009689; MedGen: C0393929; Orphanet: 590; OMIM: 254210

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001404817	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Mar 10, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001404817

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Mar 10, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV001404817.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CHAT protein function. ClinVar contains an entry for this variant (Variation ID: 958996). This missense change has been observed in individual(s) with clinical features of congenital myasthenic syndrome (CMS) (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 574 of the CHAT protein (p.Thr574Ile).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 28, 2024

ClinVar

Relating variation to medicine