Submissions for variant NM_001081.4(CUBN):c.6822-1G>A

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003076464	SCV003450452	likely pathogenic	Imerslund-Grasbeck syndrome	2022-05-13	criteria provided, single submitter	clinical testing	Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant has not been reported in the literature in individuals affected with CUBN-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 44 of the CUBN 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 CUBN are known to be pathogenic (PMID: 15024727, 22929189). 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.
Eurofins-Biomnis	RCV003236596	SCV003935044	likely pathogenic	Proteinuria, chronic benign	2022-10-14	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003410060	SCV004115574	likely pathogenic	CUBN-related disorder	2023-06-05	criteria provided, single submitter	clinical testing	The CUBN c.6822-1G>A variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. To our knowledge, this variant has not been reported in the literature or a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Variants that disrupt the consensus splice acceptor site in CUBN are expected to be pathogenic. This variant is interpreted as likely pathogenic.