ClinVar Miner

Submissions for variant NM_001081.3(CUBN):c.10102A>G (p.Met3368Val) (rs767333853)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000317510 SCV000361609 uncertain significance Imerslund-Gräsbeck syndrome 1 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx RCV000427784 SCV000536252 uncertain significance not provided 2017-01-10 criteria provided, single submitter clinical testing The M3368V variant in the CUBN gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The M3368V variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The M3368V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved across species, and in silico analysis predicts this variant likely does not alter the protein structure/function. As an alternate mechanism, multiple in silico algorithms predict that this sequence change might create an upstream cryptic splice donor site which may supplant the natural splice donor site in intron 63. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. We interpret M3368V as a variant of uncertain significance.
Invitae RCV001242144 SCV001415212 uncertain significance Imerslund-Gräsbeck syndrome 2019-09-27 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 3368 of the CUBN protein (p.Met3368Val). The methionine residue is weakly conserved and there is a small physicochemical difference between methionine and valine. This variant is present in population databases (rs767333853, ExAC 0.08%). This variant has not been reported in the literature in individuals with CUBN-related conditions. ClinVar contains an entry for this variant (Variation ID: 299368). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.

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