rs104894299
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4
The NM_005055.5(RAPSN):c.264C>A(p.Asn88Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00203 in 1,613,992 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_005055.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| RAPSN | NM_005055.5 | c.264C>A | p.Asn88Lys | missense_variant | Exon 2 of 8 | ENST00000298854.7 | NP_005046.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| RAPSN | ENST00000298854.7 | c.264C>A | p.Asn88Lys | missense_variant | Exon 2 of 8 | 1 | NM_005055.5 | ENSP00000298854.2 | ||
| RAPSN | ENST00000352508.7 | c.264C>A | p.Asn88Lys | missense_variant | Exon 2 of 6 | 1 | ENSP00000298853.3 | |||
| RAPSN | ENST00000529341.1 | c.264C>A | p.Asn88Lys | missense_variant | Exon 2 of 5 | 1 | ENSP00000431732.1 | |||
| RAPSN | ENST00000524487.5 | c.264C>A | p.Asn88Lys | missense_variant | Exon 2 of 7 | 5 | ENSP00000435551.2 |
Frequencies
GnomAD3 genomes 0.00148 AC: 225AN: 152110Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00156 AC: 391AN: 250910Hom.: 0 AF XY: 0.00141 AC XY: 192AN XY: 135702
GnomAD4 exome AF: 0.00209 AC: 3048AN: 1461764Hom.: 1 Cov.: 36 AF XY: 0.00201 AC XY: 1463AN XY: 727196
GnomAD4 genome 0.00148 AC: 225AN: 152228Hom.: 0 Cov.: 32 AF XY: 0.00132 AC XY: 98AN XY: 74426
ClinVar
Submissions by phenotype
not provided Pathogenic:13
PM3, PS3, PS4 -
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RAPSN: PM3:Very Strong, PM2:Supporting, PP1, PS3:Supporting -
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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. -
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) -
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Congenital myasthenic syndrome 11 Pathogenic:12
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. -
This variant was observed in heterozygosity with variant c.123del -
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This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PM2,PS1,PP3. -
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 -
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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). -
PS3, PM1, PM2, PP3, PP5 -
Fetal akinesia deformation sequence 1;C4225367:Congenital myasthenic syndrome 11 Pathogenic:4
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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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RAPSN protein function. Experimental studies have shown that this missense change affects RAPSN function (PMID: 16945936). For these reasons, this variant has been classified as Pathogenic. -
Congenital myasthenic syndrome Pathogenic:2Other:1
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. -
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Congenital myasthenic syndrome 4C Pathogenic:2
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. -
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Inborn genetic diseases Pathogenic:1
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. -
Congenital myasthenic syndrome 11;C4760576:Fetal akinesia deformation sequence 2 Pathogenic:1
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Fetal akinesia deformation sequence 1 Pathogenic:1
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RAPSN-related disorder Pathogenic:1
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. -
Fetal akinesia deformation sequence 2 Pathogenic:1
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Myopathy Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at