Submissions for variant NM_005055.5(RAPSN):c.848T>C (p.Leu283Pro)

gnomAD frequency: 0.00004  dbSNP: rs104894293

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000178899	SCV000231075	likely pathogenic	not provided	2015-04-16	criteria provided, single submitter	clinical testing
Génétique des Maladies du Développement, Hospices Civils de Lyon	RCV001255415	SCV001431815	pathogenic	Global developmental delay	2019-11-01	criteria provided, single submitter	clinical testing	homozygous
Athena Diagnostics Inc	RCV000178899	SCV001476804	likely pathogenic	not provided	2020-01-03	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity. Found in at least one patient with expected phenotype for this gene. Conflicting predictions of the effect on the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Baylor Genetics	RCV001336781	SCV001530270	uncertain significance	Fetal akinesia deformation sequence 1	2018-11-24	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV001731282	SCV001984839	likely pathogenic	RAPSN-Related Disorders	2020-06-29	criteria provided, single submitter	clinical testing	This variant has been previously reported as a compound heterozygous change with a splicing variant in one patient with Congenital myasthenic syndrome (CMS, PMID: 16931511). This alteration is located upstream of the coiled-coil region of rapsyn shown to be important for the interaction between rapsyn and acetylcholine receptor (AChR) (PMID: 11791205). In-vitro cotransfection studies using mammalian cells indicated that this variant significantly diminishes coclustering of AChR with rapsyn (PMID: 16931511). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.004% (10/246168) and thus is presumed to be rare. The majority of utilized in-silico tools support a deleterious effect of the c.848T>C (p.Leu283Pro) variant on protein function. Based on the available evidence, the c.848T>C (p.Leu283Pro) variant is classified as Likely Pathogenic.
Invitae	RCV002512911	SCV003275582	uncertain significance	Fetal akinesia deformation sequence 1; Congenital myasthenic syndrome 11	2022-02-08	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 283 of the RAPSN protein (p.Leu283Pro). This variant is present in population databases (rs104894293, gnomAD 0.008%). This missense change has been observed in individual(s) with congenital myasthenic syndrome (PMID: 16931511). ClinVar contains an entry for this variant (Variation ID: 8052). 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 expected to disrupt RAPSN protein function. Experimental studies have shown that this missense change affects RAPSN function (PMID: 16931511). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Revvity Omics, Revvity	RCV000178899	SCV003813745	uncertain significance	not provided	2019-03-06	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003460441	SCV004206080	likely pathogenic	Fetal akinesia deformation sequence 2	2023-10-23	criteria provided, single submitter	clinical testing
OMIM	RCV000008518	SCV000028726	pathogenic	Congenital myasthenic syndrome 11	2006-10-10	no assertion criteria provided	literature only