Submissions for variant NM_005055.5(RAPSN):c.133G>A (p.Val45Met)

gnomAD frequency: 0.00006  dbSNP: rs121909254

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000704275	SCV000833217	pathogenic	Fetal akinesia deformation sequence 1; Congenital myasthenic syndrome 11	2023-11-28	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 45 of the RAPSN protein (p.Val45Met). This variant is present in population databases (rs121909254, gnomAD 0.007%). This missense change has been observed in individual(s) with congenital myasthenic syndrome (PMID: 19620612). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8055). 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: 17594401). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002476946	SCV000893881	likely pathogenic	Congenital myasthenic syndrome 11; Fetal akinesia deformation sequence 2	2022-05-11	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000992743	SCV001145256	likely pathogenic	not provided	2019-06-21	criteria provided, single submitter	clinical testing	The best available variant frequency is uninformative because it is below the disease allele frequency. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Damaging to protein function(s) relevant to disease mechanism.
GeneDx	RCV000992743	SCV001812761	pathogenic	not provided	2021-04-23	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect with the V45M variant markedly decreasing the ability of rapsyn to cocluster with AChR subunits (Maselli et al., 2007); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 17878953, 17594401, 28492532, 19620612, 28495245, 31981491)
Revvity Omics, Revvity	RCV000992743	SCV002019020	likely pathogenic	not provided	2020-09-29	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000008521	SCV002768978	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 foetal 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 valine to methionine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD v2 <0.01 for a recessive condition (11 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated N terminal myristoylation and linker region (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed in eight individuals with RAPSN -related conditions, including one individual who was also compound heterozygous for p.(Asn88Lys) (ClinVar, PMIDs: 19620612, 17594401). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies have shown that this variant decreases the ability of RAPSN to cluster with acetylcholine receptors (PMID: 17594401). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Baylor Genetics	RCV003460442	SCV004206082	likely pathogenic	Fetal akinesia deformation sequence 2	2023-10-02	criteria provided, single submitter	clinical testing
OMIM	RCV000008521	SCV000028729	pathogenic	Congenital myasthenic syndrome 11	2007-07-01	no assertion criteria provided	literature only
Natera, Inc.	RCV001275253	SCV001460225	likely pathogenic	Congenital myasthenic syndrome	2020-09-16	no assertion criteria provided	clinical testing
Istanbul Faculty of Medicine, Istanbul University	RCV003460442	SCV004028460	pathogenic	Fetal akinesia deformation sequence 2	2022-01-10	no assertion criteria provided	clinical testing	Lethal phenotype, identified in a sibship of two