Submissions for variant NM_031229.4(RBCK1):c.1308+1G>T

dbSNP: rs1555787903

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000578499	SCV000681274	likely pathogenic	not provided	2017-12-29	criteria provided, single submitter	clinical testing	The c.1308+1G>T variant in the RBCK1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This splice site variant destroys the canonical splice donor site in intron 10. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.1308+1G>T variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.1308+1G>T as a likely pathogenic variant.
Invitae	RCV001380133	SCV001578080	pathogenic	Polyglucosan body myopathy type 1	2022-05-17	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This sequence change affects a donor splice site in intron 10 of the RBCK1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in RBCK1 are known to be pathogenic (PMID: 2379848, 23104095, 23889995). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of polyglucosan body myopathy (Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 489279). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site.