Submissions for variant NM_001081.4(CUBN):c.6125-2A>G

gnomAD frequency: 0.00226  dbSNP: rs75386064

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000428188	SCV000535408	uncertain significance	not provided	2024-10-22	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 34426522, 31613795)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000625652	SCV000943786	uncertain significance	Imerslund-Grasbeck syndrome	2022-10-20	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 40 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, 25349199, 34979989). This variant is present in population databases (rs75386064, gnomAD 0.7%), including at least one homozygous and/or hemizygous individual. Disruption of this splice site has been observed in individual(s) with clinical features of chronic proteinuria and normal renal function (PMID: 31613795). ClinVar contains an entry for this variant (Variation ID: 392184). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000428188	SCV005410948	uncertain significance	not provided	2024-09-11	criteria provided, single submitter	clinical testing	BS1, PVS1_moderate
Fulgent Genetics, Fulgent Genetics	RCV005033957	SCV005673131	likely pathogenic	Imerslund-Grasbeck syndrome type 1; Proteinuria, chronic benign	2024-05-30	criteria provided, single submitter	clinical testing
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV003993662	SCV000746155	uncertain significance	Imerslund-Grasbeck syndrome type 1	2024-04-10	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003422417	SCV004117640	uncertain significance	CUBN-related disorder	2024-02-14	no assertion criteria provided	clinical testing	The CUBN c.6125-2A>G variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with kidney disease and chronic proteinuria (Bedin et al. 2020. PubMed ID: 31613795). This variant is reported in 0.69% of alleles in individuals of African descent in gnomAD, including one homozygous observation. Other loss of function and canonical splice variants have been reported as causative both up and downstream of this change; however, these all have significantly lower frequencies in the gnomAD population. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.