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

gnomAD frequency: 0.00001  dbSNP: rs761584017

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001061762	SCV001226517	pathogenic	Fetal akinesia deformation sequence 1; Congenital myasthenic syndrome 11	2024-11-30	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 165 of the RAPSN protein (p.Val165Met). This variant is present in population databases (rs761584017, gnomAD 0.01%). This missense change has been observed in individual(s) with congenital myasthenic syndrome (PMID: 12807980, 19620612, 26927095, 29054425, 30266223). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 856323). 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) indicates that this missense variant is expected to disrupt RAPSN protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV001508667	SCV001714978	likely pathogenic	not provided	2019-07-15	criteria provided, single submitter	clinical testing	PS4_moderate, PM2, PM3
Revvity Omics, Revvity	RCV001508667	SCV002019022	likely pathogenic	not provided	2021-05-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001832551	SCV003844272	pathogenic	Congenital myasthenic syndrome	2023-02-27	criteria provided, single submitter	clinical testing	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.
Baylor Genetics	RCV003462591	SCV004206086	likely pathogenic	Fetal akinesia deformation sequence 2	2024-03-27	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005049755	SCV005684655	pathogenic	Congenital myasthenic syndrome 11; Fetal akinesia deformation sequence 2	2024-01-05	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001832551	SCV002089158	pathogenic	Congenital myasthenic syndrome	2021-03-24	no assertion criteria provided	clinical testing
Istanbul Faculty of Medicine, Istanbul University	RCV003462591	SCV004028461	pathogenic	Fetal akinesia deformation sequence 2	2022-01-10	no assertion criteria provided	clinical testing	Lethal phenotype, identified in a sibship of two