Submissions for variant NM_005055.5(RAPSN):c.271C>T (p.Arg91Cys)

gnomAD frequency: 0.00001  dbSNP: rs767507908

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000443235	SCV000521243	likely pathogenic	not provided	2017-12-26	criteria provided, single submitter	clinical testing	The R91C variant in the RAPSN gene has been reported previously in the homozygous state in an indivdiual with a congenital myasthenic syndrome (Abicht et al., 2012). The R91C variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R91C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. In addition, another missense substitution at this residue (R91L) as well as missense variants in nearby residues (N88K, E94K) have been reported in the Human Gene Mutation Database in association with congenital myasthenic syndromes (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, we interpret R91C as strong candidate for a pathogenic variantl; however, the possibility it may be a rare benign variant cannot be completely excluded.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001861510	SCV002310150	likely pathogenic	Fetal akinesia deformation sequence 1; Congenital myasthenic syndrome 11	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 91 of the RAPSN protein (p.Arg91Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with RAPSN-related conditions (PMID: 22678886, 33502061). ClinVar contains an entry for this variant (Variation ID: 381703). 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) has been performed at Invitae 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. This variant disrupts the p.Arg91 amino acid residue in RAPSN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14504330, 16945936, 31680123; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV005049547	SCV005684665	likely pathogenic	Congenital myasthenic syndrome 11; Fetal akinesia deformation sequence 2	2024-06-04	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001833532	SCV002089168	likely pathogenic	Congenital myasthenic syndrome	2021-04-21	no assertion criteria provided	clinical testing