ClinVar Miner

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

gnomAD frequency: 0.00004  dbSNP: rs104894293
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Total submissions: 9
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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 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 disorder 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.
Labcorp Genetics (formerly Invitae), Labcorp 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 2024-03-23 criteria provided, single submitter clinical testing
OMIM RCV000008518 SCV000028726 pathogenic Congenital myasthenic syndrome 11 2006-10-10 no assertion criteria provided literature only

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