ClinVar Miner

Submissions for variant NM_001081.4(CUBN):c.5428C>T (p.Arg1810Ter)

gnomAD frequency: 0.00019  dbSNP: rs143944436
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000705555 SCV000834556 pathogenic Imerslund-Grasbeck syndrome 2023-10-05 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg1810*) 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 (rs143944436, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with clinical features of Imerslund-Gräsbeck syndrome (PMID: 31613795). ClinVar contains an entry for this variant (Variation ID: 581662). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics RCV001536070 SCV001752767 pathogenic Imerslund-Grasbeck syndrome type 1; Proteinuria, chronic benign 2024-02-14 criteria provided, single submitter clinical testing
GeneDx RCV001547777 SCV001767560 likely pathogenic not provided 2024-12-16 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; This variant is associated with the following publications: (PMID: 25635822, 31589614, 35064937, 31613795, 38287090)
Revvity Omics, Revvity RCV001547777 SCV002019781 pathogenic not provided 2023-06-19 criteria provided, single submitter clinical testing
SingHealth Duke-NUS Institute of Precision Medicine RCV000705555 SCV000853127 likely pathogenic Imerslund-Grasbeck syndrome 2017-06-07 no assertion criteria provided curation
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare RCV000705555 SCV000863860 likely pathogenic Imerslund-Grasbeck syndrome 2018-05-09 no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV001547777 SCV002037528 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV001547777 SCV002037905 pathogenic not provided no assertion criteria provided clinical testing
Gene Friend Way, National Innovation Center RCV003313972 SCV004013903 likely pathogenic Autism spectrum disorder 2023-07-28 no assertion criteria provided 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. In our study, two children diagnosed with severe Autism Spectrum Disorder (ASD) are carriers of this mutation, among the two patients, one also carries another variant known to associate with ASD (SRD5A2 (rs9332964)).
PreventionGenetics, part of Exact Sciences RCV003918139 SCV004727822 pathogenic CUBN-related disorder 2023-11-29 no assertion criteria provided clinical testing The CUBN c.5428C>T variant is predicted to result in premature protein termination (p.Arg1810*). This variant was reported with a second CUBN variant in two patients with kidney disease; however, phase of the variants was not determined (Supp. Table 2 in Bedin et al. 2020. PubMed ID: 31613795). Of note, the c.5428C>T has been reported with the c.6088C>T (p.Arg2030*) variant in two patients in the literature, but segregation analysis was not completed to determine phase (Family 21, Supp Table 2 in Bedin et al. 2020. PubMed ID: 31613795; Case #20, Supp. Table 3 in Lu L et al 2022. PubMed ID: 35064937). At PreventionGenetics, we have observed the c.6088C>T and c.5428C>T variants to occur on the same allele (cis phase) based on parental follow up testing (internal data). This variant is reported in 0.024% of alleles in individuals of African descent in gnomAD. Nonsense variants in CUBN are expected to be pathogenic. This variant is interpreted as pathogenic.

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