NM_020549.5(CHAT):c.1663G>A (p.Glu555Lys) AND Familial infantile myasthenia

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Oct 26, 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:: RCV000804335.3

Allele description [Variation Report for NM_020549.5(CHAT):c.1663G>A (p.Glu555Lys)]

NM_020549.5(CHAT):c.1663G>A (p.Glu555Lys)

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.1663G>A (p.Glu555Lys)

HGVS:

NC_000010.11:g.49655123G>A
NG_011797.1:g.51029G>A
NM_001142929.2:c.1309G>A
NM_001142933.2:c.1417G>A
NM_001142934.2:c.1309G>A
NM_020549.5:c.1663G>AMANE SELECT
NM_020984.4:c.1309G>A
NM_020985.4:c.1309G>A
NM_020986.4:c.1309G>A
NP_001136401.2:p.Glu437Lys
NP_001136405.2:p.Glu473Lys
NP_001136406.2:p.Glu437Lys
NP_065574.3:p.Glu555Lys
NP_065574.4:p.Glu555Lys
NP_066264.4:p.Glu437Lys
NP_066265.4:p.Glu437Lys
NP_066266.4:p.Glu437Lys
NC_000010.10:g.50863169G>A
NM_020549.4:c.1663G>A

Protein change:

E437K

Links:

dbSNP: rs757303526

NCBI 1000 Genomes Browser:

rs757303526

Molecular consequence:

NM_001142929.2:c.1309G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001142933.2:c.1417G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001142934.2:c.1309G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_020549.5:c.1663G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_020984.4:c.1309G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_020985.4:c.1309G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_020986.4:c.1309G>A - 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

Recent activity

Clear Turn Off Turn On

Pseudochaenichthys georgianus chromosome 4, fPseGeo1.1, whole genome shotgun seq...
Pseudochaenichthys georgianus chromosome 4, fPseGeo1.1, whole genome shotgun sequence
gi|1835983138|gnl|ASM:GCF_902827114 r_scaffold_4|ref|NC_047506.1||gpp|GPC_000006890.1||gnl|NCBI_GENOMES|93112

Nucleotide

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000944239	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Oct 26, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 28497657, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000944239

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Oct 26, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

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

A rapid gene sequencing panel strategy to facilitate precision neonatal medicine.

Brunelli L, Mao R, Jenkins SM, Bleyl SB, Dames SA, Miller CE, Ostrander B, Tvrdik T, Andrews S, Flores J, Patel S, Gudgeon JM, Schaefer S.

Am J Med Genet A. 2017 Jul;173(7):1979-1982. doi: 10.1002/ajmg.a.38259. Epub 2017 May 12. No abstract available.

PubMed [citation]

PMID:: 28497657

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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000944239.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 555 of the CHAT protein (p.Glu555Lys). This variant is present in population databases (rs757303526, gnomAD 0.003%). This missense change has been observed in individual(s) with congenital myasthenic syndrome (PMID: 28497657). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 649407). 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 with a positive predictive value of 95%. 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.

#	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: Sep 29, 2024

ClinVar

Relating variation to medicine