Submissions for variant NM_005055.5(RAPSN):c.872G>A (p.Gly291Asp)

gnomAD frequency: 0.00001  dbSNP: rs374604570

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV000850590	SCV000992813	uncertain significance	Fetal akinesia deformation sequence 1; Congenital myasthenic syndrome 11	2012-08-10	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000850590	SCV002297172	likely pathogenic	Fetal akinesia deformation sequence 1; Congenital myasthenic syndrome 11	2023-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 291 of the RAPSN protein (p.Gly291Asp). This variant is present in population databases (rs374604570, gnomAD 0.004%). This missense change has been observed in individual(s) with congenital myasthenic syndrome (PMID: 12796535). 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: 689779). 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%. 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470993	SCV002768221	likely 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 Likely Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with fetal 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 glycine to aspartic acid. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 4 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v2) (highest allele count: v2: 4 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated MalT-like TPR region (DECIPHER), a linker region between the last tetratricopeptide repeat and the coiled-coil domain (PMID: 12796535). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0803 - This variant has limited previous evidence of pathogenicity. It has also been reported as a VUS in ClinVar by Baylor in an affected individual. In addition, it was detected in trans with the well-known pathogenic variant p.(Asn88Lys) in two siblings with congenital myasthenic syndrome (PMID: 12796535). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_005055.5(RAPSN):c.264C>A; p.(Asn88Lys)) in a recessive disease. (SP) 1206 - This variant has been shown to be paternally inherited (by segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Revvity Omics, Revvity	RCV003130080	SCV003813711	uncertain significance	not provided	2021-11-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV002470993	SCV003841200	likely pathogenic	Congenital myasthenic syndrome 11		criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003467529	SCV004206108	likely pathogenic	Fetal akinesia deformation sequence 2	2023-03-22	criteria provided, single submitter	clinical testing