Submissions for variant NM_001081.4(CUBN):c.6928_6934del (p.Glu2310fs)

dbSNP: rs757649673

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000169656	SCV000221183	pathogenic	Imerslund-Grasbeck syndrome	2014-12-15	criteria provided, single submitter	clinical testing	The Glu2310CysfsX3 variant is predicted to alter the protein’s amino acid sequence beginning at position 2310 and lead to a premature termination codon 3 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. In summary, this variant meets our criteria for pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169656	SCV000829160	pathogenic	Imerslund-Grasbeck syndrome	2025-01-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu2310Cysfs*3) in the CUBN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CUBN are known to be pathogenic (PMID: 15024727, 22929189, 25349199, 31613795, 34979989). This variant is present in population databases (rs757649673, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with CUBN-related conditions. ClinVar contains an entry for this variant (Variation ID: 189227). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV001535838	SCV001752441	pathogenic	Imerslund-Grasbeck syndrome type 1; Proteinuria, chronic benign	2021-06-30	criteria provided, single submitter	clinical testing
GeneDx	RCV001571327	SCV001795778	pathogenic	not provided	2024-05-28	criteria provided, single submitter	clinical testing	Identified with a second CUBN variant in a patient with persistent nephrotic proteinuria, diffuse foot process effacement of podocytes, and variable thickness of the glomerular basal membrane in published literature (PMID: 36913226); Frameshift 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; This variant is associated with the following publications: (PMID: 23685560, 31980526, 31589614, 36913226, 31613795)
Molecular Diagnostics Lab, Nemours Children's Health, Delaware	RCV004772856	SCV005382642	pathogenic	Chronic kidney disease	2021-08-12	criteria provided, single submitter	clinical testing	This variant (c.6928_6934del, p.Glu2310Cysfs*3) predicts a frameshift to a premature stop codon. It has been observed at extremely low frequency in population databases (gnomAD) and has been reported in the literature (PMID 25349199, 22929189, 15024727), although no functional studies have been reported. The change was identified as homozygous in an affected patient.
PreventionGenetics, part of Exact Sciences	RCV003927567	SCV004746207	pathogenic	CUBN-related disorder	2024-02-14	no assertion criteria provided	clinical testing	The CUBN c.6928_6934del7 variant is predicted to result in a frameshift and premature protein termination (p.Glu2310Cysfs*3). This variant has been reported along with a second truncating variant in a patient with chronic proteinuria (Table S2 of Bedin et al. 2020. PubMed ID: 31613795). This variant is reported in 0.028% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in CUBN are expected to be pathogenic. This variant is interpreted as pathogenic.