ClinVar Miner

Submissions for variant NM_001081.4(CUBN):c.3088C>A (p.Leu1030Ile)

gnomAD frequency: 0.00003  dbSNP: rs746111876
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV002273315 SCV002557108 uncertain significance Proteinuria, chronic benign 2022-02-02 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with chronic benign proteinuria (MIM#618884). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from leucine to isoleucine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (10 heterozygotes, 0 homozygotes). (SP) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools, and not conserved in placental mammals with a minor amino acid change. (SB) 0600 - Variant is located in the annotated CUB 5 domain and is a calcium binding residue (UniProt). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Labcorp Genetics (formerly Invitae), Labcorp RCV003101551 SCV003504033 uncertain significance Imerslund-Grasbeck syndrome 2022-02-18 criteria provided, single submitter clinical testing This variant has not been reported in the literature in individuals affected with CUBN-related conditions. This variant is present in population databases (rs746111876, gnomAD 0.05%). This sequence change replaces leucine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1030 of the CUBN protein (p.Leu1030Ile). 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 isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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 RCV003269151 SCV003974048 uncertain significance Inborn genetic diseases 2023-04-18 criteria provided, single submitter clinical testing The c.3088C>A (p.L1030I) alteration is located in exon 22 (coding exon 22) of the CUBN gene. This alteration results from a C to A substitution at nucleotide position 3088, causing the leucine (L) at amino acid position 1030 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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