ClinVar Miner

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

gnomAD frequency: 0.00149  dbSNP: rs104894299
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 34
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000008512 SCV000221210 pathogenic Congenital myasthenic syndrome 4C 2014-01-17 criteria provided, single submitter clinical testing 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.
Eurofins Ntd Llc (ga) RCV000224062 SCV000227353 pathogenic not provided 2018-06-19 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics RCV000224062 SCV000281522 pathogenic not provided 2014-08-22 criteria provided, single submitter clinical testing
GeneDx RCV000224062 SCV000329485 pathogenic not provided 2021-11-02 criteria provided, single submitter clinical testing 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)
Illumina Laboratory Services, Illumina RCV000170316 SCV000372475 pathogenic Congenital myasthenic syndrome 11 2017-10-17 criteria provided, single submitter clinical testing 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.
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV000414829 SCV000492841 likely pathogenic Myopathy 2015-05-05 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000477955 SCV000611311 pathogenic Fetal akinesia deformation sequence 1; Congenital myasthenic syndrome 11 2017-05-18 criteria provided, single submitter clinical testing
Invitae RCV000477955 SCV000656543 pathogenic Fetal akinesia deformation sequence 1; Congenital myasthenic syndrome 11 2024-01-31 criteria provided, single submitter clinical testing 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.
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000170316 SCV000784532 likely pathogenic Congenital myasthenic syndrome 11 2018-03-05 criteria provided, single submitter clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000286918 SCV000784533 likely pathogenic Fetal akinesia deformation sequence 1 2018-03-05 criteria provided, single submitter clinical testing
Counsyl RCV000477955 SCV000800750 pathogenic Fetal akinesia deformation sequence 1; Congenital myasthenic syndrome 11 2017-03-06 criteria provided, single submitter clinical testing
Athena Diagnostics RCV000224062 SCV001145257 pathogenic not provided 2019-06-21 criteria provided, single submitter clinical testing 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.
Baylor Genetics RCV000008512 SCV001163637 pathogenic Congenital myasthenic syndrome 4C criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000224062 SCV001245792 pathogenic not provided 2024-02-01 criteria provided, single submitter clinical testing RAPSN: PM3:Very Strong, PM2:Supporting, PP1, PS3:Supporting
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV000170316 SCV001368826 pathogenic Congenital myasthenic syndrome 11 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PM2,PS1,PP3.
Revvity Omics, Revvity RCV000224062 SCV002019642 pathogenic not provided 2023-10-26 criteria provided, single submitter clinical testing
Centogene AG - the Rare Disease Company RCV000170316 SCV002028340 pathogenic Congenital myasthenic syndrome 11 2021-08-20 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000235028 SCV002103767 pathogenic Congenital myasthenic syndrome 2022-02-01 criteria provided, single submitter clinical testing 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.
Genetics and Molecular Pathology, SA Pathology RCV000170316 SCV002556391 pathogenic Congenital myasthenic syndrome 11 2021-02-02 criteria provided, single submitter clinical testing 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).
MGZ Medical Genetics Center RCV000170316 SCV002581622 pathogenic Congenital myasthenic syndrome 11 2022-07-28 criteria provided, single submitter clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000170316 SCV002767266 pathogenic Congenital myasthenic syndrome 11 2022-02-02 criteria provided, single submitter clinical testing 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
Ambry Genetics RCV002512909 SCV003696773 pathogenic Inborn genetic diseases 2021-12-13 criteria provided, single submitter clinical testing 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; M&uuml;ller, 2003; Richard, 2003; M&uuml;ller, 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.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000170316 SCV003920984 pathogenic Congenital myasthenic syndrome 11 2023-03-29 criteria provided, single submitter clinical testing This variant was observed in heterozygosity with variant c.123del
Laboratory of Medical Genetics, National & Kapodistrian University of Athens RCV000170316 SCV004013942 pathogenic Congenital myasthenic syndrome 11 2022-10-10 criteria provided, single submitter clinical testing PS3, PM1, PM2, PP3, PP5
Baylor Genetics RCV003466838 SCV004206077 pathogenic Fetal akinesia deformation sequence 2 2024-03-30 criteria provided, single submitter clinical testing
OMIM RCV000170316 SCV000028720 pathogenic Congenital myasthenic syndrome 11 2006-12-26 no assertion criteria provided literature only
GeneReviews RCV000235028 SCV000292404 not provided Congenital myasthenic syndrome no assertion provided literature only
Division of Human Genetics, Children's Hospital of Philadelphia RCV000477955 SCV000536719 pathogenic Fetal akinesia deformation sequence 1; Congenital myasthenic syndrome 11 2016-01-26 no assertion criteria provided research
Natera, Inc. RCV000235028 SCV001460221 pathogenic Congenital myasthenic syndrome 2020-09-16 no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000224062 SCV001741814 pathogenic not provided no assertion criteria provided clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000224062 SCV001800686 pathogenic not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000224062 SCV001808376 pathogenic not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000224062 SCV001955749 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000224062 SCV001976320 pathogenic not provided no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.