ClinVar Miner

Submissions for variant NM_001081.4(CUBN):c.4366G>A (p.Asp1456Asn)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002606213 SCV003497618 uncertain significance Imerslund-Grasbeck syndrome 2022-08-09 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1456 of the CUBN protein (p.Asp1456Asn). This variant is present in population databases (rs377730376, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with CUBN-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Ambry Genetics RCV004068942 SCV004853447 likely benign Inborn genetic diseases 2024-02-14 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Fulgent Genetics, Fulgent Genetics RCV005034742 SCV005668123 uncertain significance Imerslund-Grasbeck syndrome type 1; Proteinuria, chronic benign 2024-01-09 criteria provided, single submitter clinical testing
Clinical Genomics Laboratory, Washington University in St. Louis RCV005052007 SCV005685229 uncertain significance Imerslund-Grasbeck syndrome type 1 2024-05-26 criteria provided, single submitter clinical testing A CUBN c.4366G>A (p.Asp1456Asn) variant was identified. This variant, to our knowledge, has not been reported in the medical literature. It is observed on 41/282,776 alleles in the general population (gnomAD v.2.1.1). This variant has been reported in the ClinVar database as a variant of uncertain significance by one submitter and a likely benign variant by two submitters (ClinVar ID: 2181567). Computational predictors are uncertain as to the impact of this variant on CUBN function. Due to limited information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of this variant is uncertain at this time.
PreventionGenetics, part of Exact Sciences RCV003963676 SCV004780465 likely benign CUBN-related disorder 2023-02-02 no assertion criteria provided clinical testing This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

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