VCV000008046.78 - ClinVar

NM_005055.5(RAPSN):c.264C>A (p.Asn88Lys)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(37)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_005055.5(RAPSN):c.264C>A (p.Asn88Lys)

Variation ID: 8046 Accession: VCV000008046.78

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p11.2 11: 47448079 (GRCh38) [ NCBI UCSC ] 11: 47469631 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 30, 2015	Oct 20, 2024	Mar 30, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_005055.5:c.264C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005046.2:p.Asn88Lys	missense
NM_032645.5:c.264C>A	NP_116034.2:p.Asn88Lys	missense
NC_000011.10:g.47448079G>T
NC_000011.9:g.47469631G>T
NG_008312.1:g.6100C>A
	Q13702:p.Asn88Lys

... more HGVS ... less HGVS

Protein change

N88K

Other names

p.N88K

Canonical SPDI

NC_000011.10:47448078:G:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00120 (T)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 0.00120

1000 Genomes Project 30x 0.00141

The Genome Aggregation Database (gnomAD) 0.00149

The Genome Aggregation Database (gnomAD), exomes 0.00156

Exome Aggregation Consortium (ExAC) 0.00159

Trans-Omics for Precision Medicine (TOPMed) 0.00160

Links

ClinGen: CA199511 UniProtKB: Q13702#VAR_021217 OMIM: 601592.0001 dbSNP: rs104894299 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
RAPSN		-	-	GRCh38 GRCh37	679	693

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Congenital myasthenic syndrome 4C	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jan 17, 2014	RCV000008512.18
Congenital myasthenic syndrome 11	Pathogenic/Likely pathogenic (11)	criteria provided, multiple submitters, no conflicts	Mar 29, 2023	RCV000170316.27
Congenital myasthenic syndrome	Pathogenic (3)	criteria provided, single submitter	Feb 1, 2022	RCV000235028.12
not provided	Pathogenic (12)	criteria provided, multiple submitters, no conflicts	Feb 1, 2024	RCV000224062.52
Fetal akinesia deformation sequence 1	Likely pathogenic (1)	criteria provided, single submitter	Mar 5, 2018	RCV000286918.20
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Dec 13, 2021	RCV002512909.9
Myopathy	Likely pathogenic (1)	criteria provided, single submitter	May 5, 2015	RCV000414829.10
Fetal akinesia deformation sequence 2	Pathogenic (1)	criteria provided, single submitter	Mar 30, 2024	RCV003466838.2
Congenital myasthenic syndrome 11 Fetal akinesia deformation sequence 1	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Jan 31, 2024	RCV000477955.22
RAPSN-related disorder	Pathogenic (1)	no assertion criteria provided	Jun 21, 2024	RCV004732539.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Jan 17, 2014)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Myasthenic syndrome, congenital, associated with acetylcholine receptor deficiency (Autosomal recessive inheritance) Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Study: CSER-MedSeq Accession: SCV000221210.2 First in ClinVar: Apr 01, 2015 Last updated: Jun 28, 2015	Publications: PubMed (13) PubMed: 14659409‚ 16945936‚ 12730725‚ 12807980‚ 17190963‚ 19620612‚ 20157724‚ 15482960‚ 15328566‚ 11791205‚ 12796535‚ 15036330‚ 21305573 Comment: The Asn88Lys variant in RAPSN has been previously identified in many individuals with congenital myasthenic syndrome and has been shown to segregate with disease in … (more) The Asn88Lys variant in RAPSN has been previously identified in many individuals with congenital myasthenic syndrome and has been shown to segregate with disease in several affected family members (Ohno 2002, Dunne 2003, Richard 2003, Muller 2003, Banwell 2004, Yasaki 2004, Muller 2004, Ioos 2004, Cossins 2006, Skeie 2006, Milone 2009, Brugoni 2010, Bell 2011, Alseth 2011). This variant has been identified in 0.01% (13/8596) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs104894299). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Functional studies indicate the Asn88Lys variant results in reduced co-localization with the acetylcholine receptor (AChR) (Cossins 2006). In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM) based upon segregation studies and functional evidence. (less) Number of individuals with the variant: 1
Pathogenic (Aug 22, 2014)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics Accession: SCV000281522.1 First in ClinVar: Jun 08, 2016 Last updated: Jun 08, 2016
Likely pathogenic (May 05, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Myopathy Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV000492841.1 First in ClinVar: Jan 13, 2017 Last updated: Jan 13, 2017
Pathogenic (Jun 19, 2018)	criteria provided, single submitter (EGL ClinVar v180209 classification definitions) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000227353.5 First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018	Publications: PubMed (6) PubMed: 11791205‚ 12730725‚ 12796535‚ 14504330‚ 15482960‚ 20930056 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=RAPSN Number of individuals with the variant: 8 Sex: mixed
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital myasthenic syndrome 4C Affected status: unknown Allele origin: germline	Baylor Genetics Accession: SCV001163637.1 First in ClinVar: Feb 28, 2020 Last updated: Feb 28, 2020
Pathogenic (Jan 01, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital myasthenic syndrome 11 Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001368826.2 First in ClinVar: Jul 06, 2020 Last updated: Dec 12, 2020	Comment: This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PM2,PS1,PP3.
Pathogenic (Feb 01, 2022)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Congenital myasthenic syndrome Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002103767.1 First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022	Publications: PubMed (5) PubMed: 22678886‚ 16945936‚ 12929188‚ 11791205‚ 12807980 Comment: Variant summary: RAPSN c.264C>A (p.Asn88Lys) results in a non-conservative amino acid change located in the Tetratricopeptide repeat (IPR019734) of the encoded protein sequence. Five of … (more) Variant summary: RAPSN c.264C>A (p.Asn88Lys) results in a non-conservative amino acid change located in the Tetratricopeptide repeat (IPR019734) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0016 in 250910 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in RAPSN causing Congenital Myasthenic Syndrome (0.0016 vs 0.0016). c.264C>A has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Congenital Myasthenic Syndrome and is considered a European founder mutation (e.g. Ohno_2002, Maselli_2003, Richard_2003, Cossins_2006, Abicht_2012). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant affects the association of rapsyn with AChR and dramatically reduces the stability of AChR clusters (Ohno_2002, Cossins_2006). Sixteen ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic and one ClinVar submitter (evaluation after 2014) cites it as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Feb 02, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital myasthenic syndrome 11 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Genetics and Molecular Pathology, SA Pathology Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002556391.2 First in ClinVar: Aug 08, 2022 Last updated: Dec 17, 2022	Publications: PubMed (4) PubMed: 11791205‚ 12796535‚ 14504330‚ 16945936 Comment: The RAPSN c.264C>A variant is classified as a PATHOGENIC VARIANT (PS3, PS4, PP1, PP3, PP5) This variant is a single nucleotide change from a cytosine … (more) The RAPSN c.264C>A variant is classified as a PATHOGENIC VARIANT (PS3, PS4, PP1, PP3, PP5) This variant is a single nucleotide change from a cytosine to an adenine at position 264 which is predicted to change the Asparagine at position 88 in the protein to Lysine. The variant is in exon 2 and is located in protein domain: tetratricopeptide repeat, of the RAPSN gene. This variant is a common pathogenic variant in the RAPSN gene causing congenital myasthenic syndrome (CMSs), and has been reported in many individuals with CMSs in both the homozygous or compound heterozygous state (PS4). Further, this variant has also been shown to segregate with disease in multiples families with CMSs (PP1) (PMID: 12796535, 16945936, 14504330). In vitro functional studies have demonstrated that this variant reduced the recruitment of the acetylcholine receptor (AChR) to rapsyn clusters, as well as impaired postsynaptic morphological development (PMID: 11791205, 16945936) (PS3). The variant is in dbSNP (rs104894299) and has been reported in population databases (gnomAD: 429/282254, 0 homozygote). The variant has been reported in ClinVar (Variation ID: 8046) and HGMD (Accession ID: CM020758) as pathogenic (PP5). Computational predictions support a deleterious effect on the gene or gene product (PP3). (less)
Pathogenic (Mar 29, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital myasthenic syndrome 11 (Autosomal recessive inheritance) Affected status: yes Allele origin: maternal	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne Accession: SCV003920984.1 First in ClinVar: May 06, 2023 Last updated: May 06, 2023	Comment: This variant was observed in heterozygosity with variant c.123del Method: Exome sequencing
Pathogenic (Oct 26, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002019642.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Dec 13, 2021)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV003696773.2 First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024	Publications: PubMed (9) PubMed: 11791205‚ 12730725‚ 12796535‚ 12807980‚ 12929188‚ 15286164‚ 16945936‚ 19620612‚ 20301347 Comment: The c.264C>A (p.N88K) alteration is located in exon 2 (coding exon 2) of the RAPSN gene. This alteration results from a C to A substitution … (more) The c.264C>A (p.N88K) alteration is located in exon 2 (coding exon 2) of the RAPSN gene. This alteration results from a C to A substitution at nucleotide position 264, causing the asparagine (N) at amino acid position 88 to be replaced by a lysine (K). Based on data from gnomAD, the A allele has an overall frequency of 0.15% (429/282254) total alleles studied. The highest observed frequency was 0.26% (332/128732) of European (non-Finnish) alleles. This alteration is the most common mutation causing congenital myasthenic syndrome in Europeans. It has been reported in many affected homozygotes and heterozygotes with a second RAPSN alteration (Ohno, 2002; Abicht, 2003; Dunne, 2003; Maselli, 2003; Müller, 2003; Richard, 2003; Müller, 2004; Cossins, 2006; Milone, 2009). This amino acid position is highly conserved in available vertebrate species. Functional studies demonstrated that the p.N88K alteration resulted in significantly reduced co-localization with the acetylcholine receptor (Ohno, 2002; Cossins, 2006). This alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. (less)
Pathogenic (Jan 25, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005198038.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (May 18, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Fetal akinesia deformation sequence 1 Congenital myasthenic syndrome 11 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000611311.1 First in ClinVar: Apr 23, 2017 Last updated: Apr 23, 2017
Pathogenic (Mar 06, 2017)	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) Method: clinical testing	Fetal akinesia deformation sequence 1 Congenital myasthenic syndrome 11 Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000800750.1 First in ClinVar: Aug 04, 2018 Last updated: Aug 04, 2018	Publications: PubMed (2) PubMed: 11791205‚ 16945936
Pathogenic (Oct 17, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019) Method: clinical testing	Congenital myasthenic syndrome 11 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000372475.3 First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019	Publications: PubMed (9) PubMed: 12796535‚ 12807980‚ 11791205‚ 19620612‚ 14504330‚ 17190963‚ 15286164‚ 12730725‚ 12929188 Comment: The RAPSN c.264C>A (p.Asn88Lys) variant is a well-documented pathogenic missense variant for congenital myasthenic syndrome (CMS). To date, all patients with CMS who carry a … (more) The RAPSN c.264C>A (p.Asn88Lys) variant is a well-documented pathogenic missense variant for congenital myasthenic syndrome (CMS). To date, all patients with CMS who carry a variant in the RASPN gene carry the p.Asn88Lys variant on at least one allele (Richard et al. 2003). Across a selection of the available literature, the p.Asn88Lys variant is reported in 80 out of 216 patients, including in 31 homozygotes and 49 compound heterozygotes. The variant is also reported in three asymptomatic homozygous mothers of patients (Ohno et al. 2002; Burke et al. 2003; Muller et al. 2003; Richard et al. 2003; Maselli et al. 2003; Dunne et al. 2003; Muller et al. 2004; Skeie et al. 2006; Milone et al. 2009). The p.Asn88Lys variant was found in three of 720 total controls and is reported at a frequency of 0.00398 in the European population of the 1000 Genomes Project. Haplotype analysis suggests that the p.Asn88Lys variant may be derived from a single founder event in an ancient Indo-European population (Muller et al. 2004). The Asn88 residue is conserved (Ohno et al. 2002) and is located in a leucine zipper motif which is involved in acetylcholine receptor clustering (Dunne et al. 2003). Expression studies in HEK cells showed that the p.Asn88Lys variant significantly reduced the recruitment of the acetylcholine receptor to rapsyn clusters (Ohno et al. 2002). Based on the collective evidence, the p.Asn88Lys variant is classified as pathogenic for congenital myasthenic syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
Pathogenic (Jun 21, 2019)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV001145257.1 First in ClinVar: Jan 19, 2020 Last updated: Jan 19, 2020	Publications: PubMed (24) PubMed: 11791205‚ 21305573‚ 15036330‚ 20157724‚ 16945936‚ 25194721‚ 26927095‚ 24319099‚ 29053879‚ 29189923‚ 15482960‚ 29054425‚ 17190963‚ 14659409‚ 15286164‚ 12796535‚ 26782015‚ 26910802‚ 20562457‚ 25264167‚ 12730725‚ 30266223‚ 30124556‚ 14504330 Comment: The best available variant frequency is more than 10 times the disease allele frequency, and is at least 0.1%. Statistically enriched in patients compared to … (more) The best available variant frequency is more than 10 times the disease allele frequency, and is at least 0.1%. Statistically enriched in patients compared to ethnically matched controls. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Occurs in three or more cases with a recessive pathogenic variant in the same gene. Damaging to protein function(s) relevant to disease mechanism. Very strong co-segregation with disease in affected individuals from a single family. (less)
Pathogenic (Aug 20, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital myasthenic syndrome 11 Affected status: yes Allele origin: germline	Centogene AG - the Rare Disease Company Accession: SCV002028340.1 First in ClinVar: Dec 04, 2021 Last updated: Dec 04, 2021
Pathogenic (Jul 28, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital myasthenic syndrome 11 Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002581622.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PS3, PM3_STR, PP1, PP3	Number of individuals with the variant: 2 Sex: male
Likely pathogenic (Mar 05, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital myasthenic syndrome 11 Affected status: yes Allele origin: inherited	Genomic Research Center, Shahid Beheshti University of Medical Sciences Accession: SCV000784532.2 First in ClinVar: Oct 11, 2015 Last updated: Dec 11, 2022	Number of individuals with the variant: 1 Age: 0-9 years Sex: female Geographic origin: Iran
Likely pathogenic (Mar 05, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Fetal akinesia deformation sequence 1 Affected status: yes Allele origin: inherited	Genomic Research Center, Shahid Beheshti University of Medical Sciences Accession: SCV000784533.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 11, 2022	Number of individuals with the variant: 1 Age: 0-9 years Sex: female Geographic origin: Iran
Pathogenic (Feb 02, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital myasthenic syndrome 11 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002767266.1 First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022	Publications: PubMed (1) PubMed: 29054425 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with fetal akinesia deformation sequence 2 (MIM#618388) and congenital myasthenic syndrome 11 associated with acetylcholine receptor deficiency (MIM#616326). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from asparagine to lysine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 429 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It is a well-known pathogenic variant, and it has been reported in multiple individuals with congenital myasthenic syndrome (ClinVar, PMID: 29054425). (SP) 1205 - This variant has been shown to be maternally inherited (by segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
Pathogenic (Nov 02, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000329485.8 First in ClinVar: Dec 06, 2016 Last updated: Mar 04, 2023	Comment: Published functional studies demonstrate a damaging effect, including diminished coclustering of AChR with rapsyn and impaired post-synaptic morphological development (Ohno et al., 2002; Cossins et … (more) Published functional studies demonstrate a damaging effect, including diminished coclustering of AChR with rapsyn and impaired post-synaptic morphological development (Ohno et al., 2002; Cossins et al., 2006); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 15328566, 12730725, 19620612, 25194721, 15482960, 11791205, 29053879, 16945936, 21228398, 12929188, 24319099, 20157724, 15286164, 26927095, 15036330, 12796535, 12807980, 17190963, 14659409, 21305573, 29189923, 29054425, 30266223, 30028532, 31226102, 27397848, 32070632, 31980526, 32403337, 31127727, 32528171) (less)
Pathogenic (Oct 10, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital myasthenic syndrome 11 Affected status: yes Allele origin: germline	Laboratory of Medical Genetics, National & Kapodistrian University of Athens Accession: SCV004013942.1 First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023	Comment: PS3, PM1, PM2, PP3, PP5
Pathogenic (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Congenital myasthenic syndrome 11 Fetal akinesia deformation sequence 1 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000656543.9 First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024	Publications: PubMed (4) PubMed: 28492532‚ 12796535‚ 14504330‚ 16945936 Comment: This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 88 of the RAPSN protein (p.Asn88Lys). … (more) This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 88 of the RAPSN protein (p.Asn88Lys). This variant is present in population databases (rs104894299, gnomAD 0.3%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with congenital myasthenic syndrome (PMID: 12796535, 14504330, 16945936). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of European ancestry (PMID: 12796535, 14504330, 16945936). ClinVar contains an entry for this variant (Variation ID: 8046). 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 not expected to disrupt RAPSN protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects RAPSN function (PMID: 16945936). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Mar 30, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Fetal akinesia deformation sequence 2 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004206077.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Feb 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001245792.26 First in ClinVar: May 09, 2020 Last updated: Oct 20, 2024	Comment: RAPSN: PM3:Very Strong, PM2:Supporting, PP1, PS3:Supporting Number of individuals with the variant: 8
Pathogenic (Dec 26, 2006)	no assertion criteria provided Method: literature only	MYASTHENIC SYNDROME, CONGENITAL, 11, ASSOCIATED WITH ACETYLCHOLINE RECEPTOR DEFICIENCY Affected status: not provided Allele origin: germline	OMIM Accession: SCV000028720.2 First in ClinVar: Apr 04, 2013 Last updated: Apr 30, 2015	Publications: PubMed (6) PubMed: 11791205‚ 15286164‚ 12730725‚ 12796535‚ 14504330‚ 17190963 Comment on evidence: In 2 patients with congenital myasthenic syndrome-11 (CMS11; 616326) associated with AChR deficiency, Ohno et al. (2002) identified a homozygous asn88-to-lys (N88K) mutation in the … (more) In 2 patients with congenital myasthenic syndrome-11 (CMS11; 616326) associated with AChR deficiency, Ohno et al. (2002) identified a homozygous asn88-to-lys (N88K) mutation in the RAPSN gene. The N88K mutation was identified in the compound heterozygous state with leu14-to-pro (L14P; 601592.0002) in one patient and with 553ins5 (601592.0003) in another. The N88K substitution results from a 264C-A transversion in exon 2 of the RAPSN gene (Muller et al., 2004). Dunne and Maselli (2003) identified the N88K mutation in each of 4 patients from 4 different families with CMS and AChR deficiency. One patient was homozygous for N88K and was only mildly affected, whereas the other 3 patients were heterozygous for N88K and a second mutation (L14P; 601592.0002), (46insC; 601592.0004), or (Y269X; 601592.0005) and were severely affected. The authors noted that the N88K mutation occurs within the putative leucine zipper motif, which is important for clustering of the acetylcholine receptor. Among 120 CMS patients from 110 unrelated families, Muller et al. (2003) identified the N88K mutation in 12 patients (10%) from 10 families. Seven patients were homozygous for the mutation and 5 patients were compound heterozygous. Genotype analysis of the region of chromosome 11 close to the RAPSN gene suggested that the N88K allele derived from a common European ancestor. Burke et al. (2003) reported 16 patients with CMS caused by the N88K mutation: 7 were homozygous and 9 were compound heterozygous. By haplotype analysis of 21 CMS patients of European and Indian origin with the N88K mutation, Muller et al. (2004) identified a core founder haplotype of 10 SNPs encompassing a region of 0.36 Mb flanking the mutation and concluded that N88K derived from a single founder event in an ancient Indo-European population. Skeie et al. (2006) reported a boy with an unusually mild CMS phenotype who was homozygous for the N88K mutation. Until age 5 years, he had repeated episodes of weakness with respiratory insufficiency and swallowing difficulties associated with febrile illnesses. By age 19, he participated in normal physical activity, experiencing only occasional muscle cramps and ptosis. He was always symptom-free between attacks and had normal serologic tests, normal acetylcholine receptor levels, no decrement on repetitive muscle stimulation, and no response to acetylcholinesterase inhibitors. The findings expanded the phenotype associated with the N88K mutation. (less)
Pathogenic (Jan 26, 2016)	no assertion criteria provided Method: research	Congenital myasthenic syndrome 11 Fetal akinesia deformation sequence 1 Affected status: unknown Allele origin: germline	Division of Human Genetics, Children's Hospital of Philadelphia Study: CSER-PediSeq Accession: SCV000536719.1 First in ClinVar: Apr 23, 2017 Last updated: Apr 23, 2017	Publications: PubMed (7) PubMed: 11791205‚ 21305573‚ 21228398‚ 20157724‚ 16945936‚ 25194721‚ 24319099
Pathogenic (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Congenital myasthenic syndrome Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001460221.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Study: VKGL Data-share Consensus Accession: SCV001800686.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, Amsterdam University Medical Center Study: VKGL Data-share Consensus Accession: SCV001808376.1 First in ClinVar: Aug 27, 2021 Last updated: Aug 27, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001741814.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001955749.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Pathogenic (Oct 19, 2023)	no assertion criteria provided Method: clinical testing	Congenital myasthenic syndrome 11 Affected status: yes Allele origin: maternal	Undiagnosed Diseases Network, NIH Study: Undiagnosed Diseases Network (NIH), UDN Accession: SCV005368706.1 First in ClinVar: Oct 13, 2024 Last updated: Oct 13, 2024	Number of individuals with the variant: 1 Clinical Features: Open mouth (present) , High palate (present) , Micrognathia (present) , Low-set ears (present) , Ptosis (present) , Neonatal hypotonia (present) , Joint hypermobility (present) … (more) Open mouth (present) , High palate (present) , Micrognathia (present) , Low-set ears (present) , Ptosis (present) , Neonatal hypotonia (present) , Joint hypermobility (present) , Pes planus (present) , Myalgia (present) , Prominent forehead (present) , Thin corpus callosum (present) , Long fingers (present) , Bilateral facial palsy (present) (less) Age: 0-9 years Sex: male Tissue: Blood
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001976320.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021
Pathogenic (Jun 21, 2024)	no assertion criteria provided Method: clinical testing	RAPSN-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005364025.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The RAPSN c.264C>A variant is predicted to result in the amino acid substitution p.Asn88Lys. This variant has been reported, in the compound heterozygous or homozygous … (more) The RAPSN c.264C>A variant is predicted to result in the amino acid substitution p.Asn88Lys. This variant has been reported, in the compound heterozygous or homozygous state, as a recurrent RAPSN variant in many individuals with autosomal recessive congenital myasthenic syndrome (Ohno et al. 2002. PubMed ID: 11791205; Ohno et al. 2004. PubMed ID: 14729848; Brugnoni et al. 2010. PubMed ID: 20157724; Laquérriere. 2014. PubMed ID: 24319099; Natera-de Benito. 2017. PubMed ID: 29054425; McMacken. 2018. PubMed ID: 29189923). Functional studies suggest that the p.Asn88Lys variant results in reduced stability of the AChR clusters (Cossins. 2006. PubMed ID: 16945936). This variant is reported in 0.26% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. (less)
not provided (-)	no classification provided Method: literature only	Congenital myasthenic syndrome Affected status: yes Allele origin: germline	GeneReviews Accession: SCV000292404.2 First in ClinVar: Jul 19, 2016 Last updated: Oct 01, 2022	Publications: PubMed (4) PubMed: 12807980‚ 14729848‚ 15482960‚ 12651869 BookShelf: NBK1168 BookShelf: NBK1168
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Comment:

The Asn88Lys variant in RAPSN has been previously identified in many individuals with congenital myasthenic syndrome and has been shown to segregate with disease in several affected family members (Ohno 2002, Dunne 2003, Richard 2003, Muller 2003, Banwell 2004, Yasaki 2004, Muller 2004, Ioos 2004, Cossins 2006, Skeie 2006, Milone 2009, Brugoni 2010, Bell 2011, Alseth 2011). This variant has been identified in 0.01% (13/8596) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs104894299). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Functional studies indicate the Asn88Lys variant results in reduced co-localization with the acetylcholine receptor (AChR) (Cossins 2006). In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM) based upon segregation studies and functional evidence.

Comment:

Variant summary: RAPSN c.264C>A (p.Asn88Lys) results in a non-conservative amino acid change located in the Tetratricopeptide repeat (IPR019734) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0016 in 250910 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in RAPSN causing Congenital Myasthenic Syndrome (0.0016 vs 0.0016). c.264C>A has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Congenital Myasthenic Syndrome and is considered a European founder mutation (e.g. Ohno_2002, Maselli_2003, Richard_2003, Cossins_2006, Abicht_2012). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant affects the association of rapsyn with AChR and dramatically reduces the stability of AChR clusters (Ohno_2002, Cossins_2006). Sixteen ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic and one ClinVar submitter (evaluation after 2014) cites it as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

The RAPSN c.264C>A variant is classified as a PATHOGENIC VARIANT (PS3, PS4, PP1, PP3, PP5) This variant is a single nucleotide change from a cytosine to an adenine at position 264 which is predicted to change the Asparagine at position 88 in the protein to Lysine. The variant is in exon 2 and is located in protein domain: tetratricopeptide repeat, of the RAPSN gene. This variant is a common pathogenic variant in the RAPSN gene causing congenital myasthenic syndrome (CMSs), and has been reported in many individuals with CMSs in both the homozygous or compound heterozygous state (PS4). Further, this variant has also been shown to segregate with disease in multiples families with CMSs (PP1) (PMID: 12796535, 16945936, 14504330). In vitro functional studies have demonstrated that this variant reduced the recruitment of the acetylcholine receptor (AChR) to rapsyn clusters, as well as impaired postsynaptic morphological development (PMID: 11791205, 16945936) (PS3). The variant is in dbSNP (rs104894299) and has been reported in population databases (gnomAD: 429/282254, 0 homozygote). The variant has been reported in ClinVar (Variation ID: 8046) and HGMD (Accession ID: CM020758) as pathogenic (PP5). Computational predictions support a deleterious effect on the gene or gene product (PP3).

Comment:

The c.264C>A (p.N88K) alteration is located in exon 2 (coding exon 2) of the RAPSN gene. This alteration results from a C to A substitution at nucleotide position 264, causing the asparagine (N) at amino acid position 88 to be replaced by a lysine (K). Based on data from gnomAD, the A allele has an overall frequency of 0.15% (429/282254) total alleles studied. The highest observed frequency was 0.26% (332/128732) of European (non-Finnish) alleles. This alteration is the most common mutation causing congenital myasthenic syndrome in Europeans. It has been reported in many affected homozygotes and heterozygotes with a second RAPSN alteration (Ohno, 2002; Abicht, 2003; Dunne, 2003; Maselli, 2003; Müller, 2003; Richard, 2003; Müller, 2004; Cossins, 2006; Milone, 2009). This amino acid position is highly conserved in available vertebrate species. Functional studies demonstrated that the p.N88K alteration resulted in significantly reduced co-localization with the acetylcholine receptor (Ohno, 2002; Cossins, 2006). This alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

Comment:

The RAPSN c.264C>A (p.Asn88Lys) variant is a well-documented pathogenic missense variant for congenital myasthenic syndrome (CMS). To date, all patients with CMS who carry a variant in the RASPN gene carry the p.Asn88Lys variant on at least one allele (Richard et al. 2003). Across a selection of the available literature, the p.Asn88Lys variant is reported in 80 out of 216 patients, including in 31 homozygotes and 49 compound heterozygotes. The variant is also reported in three asymptomatic homozygous mothers of patients (Ohno et al. 2002; Burke et al. 2003; Muller et al. 2003; Richard et al. 2003; Maselli et al. 2003; Dunne et al. 2003; Muller et al. 2004; Skeie et al. 2006; Milone et al. 2009). The p.Asn88Lys variant was found in three of 720 total controls and is reported at a frequency of 0.00398 in the European population of the 1000 Genomes Project. Haplotype analysis suggests that the p.Asn88Lys variant may be derived from a single founder event in an ancient Indo-European population (Muller et al. 2004). The Asn88 residue is conserved (Ohno et al. 2002) and is located in a leucine zipper motif which is involved in acetylcholine receptor clustering (Dunne et al. 2003). Expression studies in HEK cells showed that the p.Asn88Lys variant significantly reduced the recruitment of the acetylcholine receptor to rapsyn clusters (Ohno et al. 2002). Based on the collective evidence, the p.Asn88Lys variant is classified as pathogenic for congenital myasthenic syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Comment:

The best available variant frequency is more than 10 times the disease allele frequency, and is at least 0.1%. Statistically enriched in patients compared to ethnically matched controls. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Occurs in three or more cases with a recessive pathogenic variant in the same gene. Damaging to protein function(s) relevant to disease mechanism. Very strong co-segregation with disease in affected individuals from a single family.

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with fetal akinesia deformation sequence 2 (MIM#618388) and congenital myasthenic syndrome 11 associated with acetylcholine receptor deficiency (MIM#616326). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from asparagine to lysine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 429 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It is a well-known pathogenic variant, and it has been reported in multiple individuals with congenital myasthenic syndrome (ClinVar, PMID: 29054425). (SP) 1205 - This variant has been shown to be maternally inherited (by segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Comment:

Published functional studies demonstrate a damaging effect, including diminished coclustering of AChR with rapsyn and impaired post-synaptic morphological development (Ohno et al., 2002; Cossins et al., 2006); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 15328566, 12730725, 19620612, 25194721, 15482960, 11791205, 29053879, 16945936, 21228398, 12929188, 24319099, 20157724, 15286164, 26927095, 15036330, 12796535, 12807980, 17190963, 14659409, 21305573, 29189923, 29054425, 30266223, 30028532, 31226102, 27397848, 32070632, 31980526, 32403337, 31127727, 32528171)

Comment:

This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 88 of the RAPSN protein (p.Asn88Lys). This variant is present in population databases (rs104894299, gnomAD 0.3%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with congenital myasthenic syndrome (PMID: 12796535, 14504330, 16945936). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of European ancestry (PMID: 12796535, 14504330, 16945936). ClinVar contains an entry for this variant (Variation ID: 8046). 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 not expected to disrupt RAPSN protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects RAPSN function (PMID: 16945936). For these reasons, this variant has been classified as Pathogenic.

Comment:

The RAPSN c.264C>A variant is predicted to result in the amino acid substitution p.Asn88Lys. This variant has been reported, in the compound heterozygous or homozygous state, as a recurrent RAPSN variant in many individuals with autosomal recessive congenital myasthenic syndrome (Ohno et al. 2002. PubMed ID: 11791205; Ohno et al. 2004. PubMed ID: 14729848; Brugnoni et al. 2010. PubMed ID: 20157724; Laquérriere. 2014. PubMed ID: 24319099; Natera-de Benito. 2017. PubMed ID: 29054425; McMacken. 2018. PubMed ID: 29189923). Functional studies suggest that the p.Asn88Lys variant results in reduced stability of the AChR clusters (Cossins. 2006. PubMed ID: 16945936). This variant is reported in 0.26% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Congenital Myasthenic Syndromes Overview.	Adam MP	-	2021	PMID: 20301347
Clinical variability of early-onset congenital myasthenic syndrome due to biallelic RAPSN mutations in Brazil.	Estephan EP	Neuromuscular disorders : NMD	2018	PMID: 30266223
Congenital Myasthenic Syndrome: Spectrum of Mutations in an Indian Cohort.	Selvam P	Journal of clinical neuromuscular disease	2018	PMID: 30124556
Congenital myasthenic syndrome with episodic apnoea: clinical, neurophysiological and genetic features in the long-term follow-up of 19 patients.	McMacken G	Journal of neurology	2018	PMID: 29189923
Decrement with high frequency repetitive nerve stimulation in a RAPSN congenital myasthenic syndrome.	LoRusso SJ	Muscle & nerve	2018	PMID: 29053879
Molecular characterization of congenital myasthenic syndromes in Spain.	Natera-de Benito D	Neuromuscular disorders : NMD	2017	PMID: 29054425
Potentially Treatable Disorder Diagnosed Post Mortem by Exome Analysis in a Boy with Respiratory Distress.	Imperatore V	International journal of molecular sciences	2016	PMID: 26927095
Late presentations of congenital myasthenic syndromes: How many do we miss?	Garg N	Muscle & nerve	2016	PMID: 26910802
Long-term follow-up in patients with congenital myasthenic syndrome due to RAPSN mutations.	Natera-de Benito D	Neuromuscular disorders : NMD	2016	PMID: 26782015
Congenital myasthenic syndrome in Japan: ethnically unique mutations in muscle nicotinic acetylcholine receptor subunits.	Azuma Y	Neuromuscular disorders : NMD	2015	PMID: 25264167
Use of next-generation sequencing as a diagnostic tool for congenital myasthenic syndrome.	Das AS	Pediatric neurology	2014	PMID: 25194721
Mutations in CNTNAP1 and ADCY6 are responsible for severe arthrogryposis multiplex congenita with axoglial defects.	Laquérriere A	Human molecular genetics	2014	PMID: 24319099
Congenital myasthenic syndromes: achievements and limitations of phenotype-guided gene-after-gene sequencing in diagnostic practice: a study of 680 patients.	Abicht A	Human mutation	2012	PMID: 22678886
Investigation for RAPSN and DOK-7 mutations in a cohort of seronegative myasthenia gravis patients.	Alseth EH	Muscle & nerve	2011	PMID: 21305573
Carrier testing for severe childhood recessive diseases by next-generation sequencing.	Bell CJ	Science translational medicine	2011	PMID: 21228398
Multiexon deletions account for 15% of congenital myasthenic syndromes with RAPSN mutations after negative DNA sequencing.	Gaudon K	Journal of medical genetics	2010	PMID: 20930056
Molecular characterisation of congenital myasthenic syndromes in Southern Brazil.	Mihaylova V	Journal of neurology, neurosurgery, and psychiatry	2010	PMID: 20562457
Identification of previously unreported mutations in CHRNA1, CHRNE and RAPSN genes in three unrelated Italian patients with congenital myasthenic syndromes.	Brugnoni R	Journal of neurology	2010	PMID: 20157724
Myasthenic syndrome due to defects in rapsyn: Clinical and molecular findings in 39 patients.	Milone M	Neurology	2009	PMID: 19620612
Unusual features in a boy with the rapsyn N88K mutation.	Skeie GO	Neurology	2006	PMID: 17190963
Diverse molecular mechanisms involved in AChR deficiency due to rapsyn mutations.	Cossins J	Brain : a journal of neurology	2006	PMID: 16945936
A newly identified chromosomal microdeletion of the rapsyn gene causes a congenital myasthenic syndrome.	Müller JS	Neuromuscular disorders : NMD	2004	PMID: 15482960
Congenital myasthenic syndrome due to rapsyn deficiency: three cases with arthrogryposis and bulbar symptoms.	Ioos C	Neuropediatrics	2004	PMID: 15328566
The congenital myasthenic syndrome mutation RAPSN N88K derives from an ancient Indo-European founder.	Müller JS	Journal of medical genetics	2004	PMID: 15286164
Novel truncating RAPSN mutations causing congenital myasthenic syndrome responsive to 3,4-diaminopyridine.	Banwell BL	Neuromuscular disorders : NMD	2004	PMID: 15036330
Lack of founder haplotype for the rapsyn N88K mutation: N88K is an ancient founder mutation or arises from multiple founders.	Ohno K	Journal of medical genetics	2004	PMID: 14729848
Electrophysiological and morphological characterization of a case of autosomal recessive congenital myasthenic syndrome with acetylcholine receptor deficiency due to a N88K rapsyn homozygous mutation.	Yasaki E	Neuromuscular disorders : NMD	2004	PMID: 14659409
Rapsyn mutations in hereditary myasthenia: distinct early- and late-onset phenotypes.	Burke G	Neurology	2003	PMID: 14504330
Rapsyn mutations in myasthenic syndrome due to impaired receptor clustering.	Maselli RA	Muscle & nerve	2003	PMID: 12929188
Possible founder effect of rapsyn N88K mutation and identification of novel rapsyn mutations in congenital myasthenic syndromes.	Richard P	Journal of medical genetics	2003	PMID: 12807980
Rapsyn N88K is a frequent cause of congenital myasthenic syndromes in European patients.	Müller JS	Neurology	2003	PMID: 12796535
Identification of pathogenic mutations in the human rapsyn gene.	Dunne V	Journal of human genetics	2003	PMID: 12730725
E-box mutations in the RAPSN promoter region in eight cases with congenital myasthenic syndrome.	Ohno K	Human molecular genetics	2003	PMID: 12651869
Rapsyn mutations in humans cause endplate acetylcholine-receptor deficiency and myasthenic syndrome.	Ohno K	American journal of human genetics	2002	PMID: 11791205
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=RAPSN	-	-	-	-
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Text-mined citations for rs104894299 ...

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Record last updated Nov 03, 2024

ClinVar Genomic variation as it relates to human health

NM_005055.5(RAPSN):c.264C>A (p.Asn88Lys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs104894299 ...