NM_003055.3(SLC18A3):c.557G>C (p.Gly186Ala) AND Congenital myasthenic syndrome 21

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: May 27, 2020
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:: RCV000412561.12

Allele description [Variation Report for NM_003055.3(SLC18A3):c.557G>C (p.Gly186Ala)]

NM_003055.3(SLC18A3):c.557G>C (p.Gly186Ala)

Genes:

CHAT:choline O-acetyltransferase [Gene - OMIM - HGNC]
SLC18A3:solute carrier family 18 member A3 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

10q11.23

Genomic location:

Preferred name:

NM_003055.3(SLC18A3):c.557G>C (p.Gly186Ala)

HGVS:

NC_000010.11:g.49611297G>C
NG_011797.1:g.7203G>C
NG_011797.2:g.7204G>C
NG_053144.1:g.5997G>C
NG_119460.1:g.116G>C
NM_003055.3:c.557G>CMANE SELECT
NM_020984.4:c.-69+2098G>C
NP_003046.2:p.Gly186Ala
NC_000010.10:g.50819343G>C
NM_003055.2:c.557G>C
NM_003055.3(SLC18A3):c.557G>CMANE SELECT
p.Gly186Ala

Protein change:

G186A; GLY186ALA

Links:

OMIM: 600336.0001; dbSNP: rs1057517665

NCBI 1000 Genomes Browser:

rs1057517665

Molecular consequence:

NM_020984.4:c.-69+2098G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_003055.3:c.557G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Congenital myasthenic syndrome 21
Synonyms:: Myasthenic syndrome, congenital, 21, presynaptic
Identifiers:: MONDO: MONDO:0014983; MedGen: C4310654; OMIM: 617239

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000490232	OMIM	no assertion criteria provided	Pathogenic (Dec 6, 2016)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV001430743	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (May 27, 2020)	germline	research	PubMed (2) [See all records that cite these PMIDs] 27590285, 25741868 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000490232

OMIM

no assertion criteria provided

Pathogenic
(Dec 6, 2016)

germline

literature only

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

SCV001430743

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(May 27, 2020)

germline

research

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

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	research

Citations

PubMed

Variants in SLC18A3, vesicular acetylcholine transporter, cause congenital myasthenic syndrome.

O'Grady GL, Verschuuren C, Yuen M, Webster R, Menezes M, Fock JM, Pride N, Best HA, Benavides Damm T, Turner C, Lek M, Engel AG, North KN, Clarke NF, MacArthur DG, Kamsteeg EJ, Cooper ST.

Neurology. 2016 Oct 4;87(14):1442-1448. Epub 2016 Sep 2.

PubMed [citation]

PMID:: 27590285
PMCID:: PMC5075972

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From OMIM, SCV000490232.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a boy, born of unrelated Filipino parents, with presynaptic congenital myasthenic syndrome-21 (CMS21; 617239), O'Grady et al. (2016) identified a heterozygous c.557G-C transversion (c.557G-C, NM_003055.2) in the SLC18A3 gene, resulting in a gly186-to-ala (G186A) substitution at a highly conserved residue in the fourth transmembrane domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the Exome Variant Server or the ExAC databases. The mutation was inherited from the unaffected mother. The other allele in the patient had a 4.83-Mb deletion encompassing 4 genes, including SLC18A3 and CHAT. DNA from the father was unavailable. Functional studies of the variants and studies of patient cells were not performed.

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

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001430743.1

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

Description

The heterozygous p.Gly186Ala variant in SLC18A3 was identified by our study, in the compound heterozygous state, along with a pathogenic deletion, in an individual with autosomal recessive congenital myasthenic syndrome (PMID: 27590285). It is of note that the deletion spans across at least 5 genes including SLC18A3. The p.Gly186Ala variant has been reported pathogenic by OMIM in ClinVar (Variation ID: 372159) and was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine impact. Furthermore, although this gene has been reported in association with congenital myasthenic syndrome, it currently has moderate evidence for these associations. In summary, the clinical significance of the p.Gly186Ala variant is uncertain.

#	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: Oct 26, 2024

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