NM_005055.5(RAPSN):c.493G>A (p.Val165Met) AND Congenital myasthenic syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Feb 27, 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:: RCV001832551.10

Allele description [Variation Report for NM_005055.5(RAPSN):c.493G>A (p.Val165Met)]

NM_005055.5(RAPSN):c.493G>A (p.Val165Met)

Gene:

RAPSN:receptor associated protein of the synapse [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11p11.2

Genomic location:

Preferred name:

NM_005055.5(RAPSN):c.493G>A (p.Val165Met)

HGVS:

NC_000011.10:g.47447850C>T
NG_008312.1:g.6329G>A
NM_005055.5:c.493G>AMANE SELECT
NM_032645.5:c.493G>A
NP_005046.2:p.Val165Met
NP_116034.2:p.Val165Met
NC_000011.9:g.47469402C>T
NM_005055.4:c.493G>A
p.Val165Met

Protein change:

V165M

Links:

dbSNP: rs761584017

NCBI 1000 Genomes Browser:

rs761584017

Molecular consequence:

NM_005055.5:c.493G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_032645.5:c.493G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Congenital myasthenic syndrome (CMS)
Identifiers:: MONDO: MONDO:0018940; MeSH: D020294; MedGen: C0751882; OMIM: PS601462

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002089158	Natera, Inc.	no assertion criteria provided	Pathogenic (Mar 24, 2021)	germline	clinical testing
SCV003844272	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Feb 27, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 19620612, 29054425, 22678886, 12807980, 17878953, 30266223, 26927095 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002089158

Natera, Inc.

no assertion criteria provided

Pathogenic
(Mar 24, 2021)

germline

clinical testing

SCV003844272

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Feb 27, 2023)

germline

clinical testing

PubMed (7)
[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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Myasthenic syndrome due to defects in rapsyn: Clinical and molecular findings in 39 patients.

Milone M, Shen XM, Selcen D, Ohno K, Brengman J, Iannaccone ST, Harper CM, Engel AG.

Neurology. 2009 Jul 21;73(3):228-35. doi: 10.1212/WNL.0b013e3181ae7cbc.

PubMed [citation]

PMID:: 19620612
PMCID:: PMC2715575

Molecular characterization of congenital myasthenic syndromes in Spain.

Natera-de Benito D, Töpf A, Vilchez JJ, González-Quereda L, Domínguez-Carral J, Díaz-Manera J, Ortez C, Bestué M, Gallano P, Dusl M, Abicht A, Müller JS, Senderek J, García-Ribes A, Muelas N, Evangelista T, Azuma Y, McMacken G, Paipa Merchan A, Rodríguez Cruz PM, Camacho A, Jiménez E, et al.

Neuromuscul Disord. 2017 Dec;27(12):1087-1098. doi: 10.1016/j.nmd.2017.08.003. Epub 2017 Aug 18.

PubMed [citation]

PMID:: 29054425

See all PubMed Citations (7)

Details of each submission

From Natera, Inc., SCV002089158.1

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

#	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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV003844272.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

Variant summary: RAPSN c.493G>A (p.Val165Met) results in a conservative amino acid change located in the MalT-like TPR region (IPR041617) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 247282 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.493G>A has been reported in the literature in multiple individuals affected with Congenital Myasthenic Syndrome (e.g., Richard_2003, Milone_2009, Abicht_2012, Estephan_2018, Natera-deBenito_2017, Denning_2007, Imperatore_2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) have cited the variant, and all laboratories classified the variant as pathogenic (n = 2) or likely pathogenic (n = 2). Based on the evidence outlined above, the variant was classified as 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: Apr 13, 2025

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