ClinVar Miner

Submissions for variant NM_001081.4(CUBN):c.4423A>G (p.Met1475Val)

gnomAD frequency: 0.00004  dbSNP: rs1290241240
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV001106382 SCV001263445 uncertain significance Imerslund-Grasbeck syndrome type 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.
Fulgent Genetics, Fulgent Genetics RCV002497516 SCV002797081 uncertain significance Imerslund-Grasbeck syndrome type 1; Proteinuria, chronic benign 2021-12-25 criteria provided, single submitter clinical testing
Invitae RCV002555043 SCV003267824 uncertain significance Imerslund-Grasbeck syndrome 2022-02-10 criteria provided, single submitter clinical testing 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 879149). This variant has not been reported in the literature in individuals affected with CUBN-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.006%). This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1475 of the CUBN protein (p.Met1475Val).
Ambry Genetics RCV002558070 SCV003651985 uncertain significance Inborn genetic diseases 2022-09-28 criteria provided, single submitter clinical testing The c.4423A>G (p.M1475V) alteration is located in exon 30 (coding exon 30) of the CUBN gene. This alteration results from a A to G substitution at nucleotide position 4423, causing the methionine (M) at amino acid position 1475 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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