Submissions for variant NM_005055.5(RAPSN):c.370C>T (p.Gln124Ter)

dbSNP: rs1479498379

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000534807	SCV000656545	pathogenic	Fetal akinesia deformation sequence 1; Congenital myasthenic syndrome 11	2023-08-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln124*) in the RAPSN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RAPSN are known to be pathogenic (PMID: 17686188). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with congenital myasthenic syndrome (PMID: 14504330). 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: 476121). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003114675	SCV003800989	likely pathogenic	Congenital myasthenic syndrome	2023-01-16	criteria provided, single submitter	clinical testing	Variant summary: RAPSN c.370C>T (p.Gln124X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4e-06 in 250446 control chromosomes (gnomAD). c.370C>T has been reported in the literature in the compound heterozygous state with a common pathogenic variant (p.N88K) in at least one individual affected with Congenital Myasthenic Syndrome (Burke_2003). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted a clinical-significance assessment for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV003470767	SCV004206101	pathogenic	Fetal akinesia deformation sequence 2	2023-06-28	criteria provided, single submitter	clinical testing
GeneDx	RCV004719872	SCV005324898	pathogenic	not provided	2024-02-06	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 36815443, 14504330)