ClinVar Miner

Submissions for variant NM_001081.4(CUBN):c.3646C>G (p.Pro1216Ala)

gnomAD frequency: 0.00027  dbSNP: rs145881708
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000803662 SCV000943544 uncertain significance Imerslund-Grasbeck syndrome 2023-02-28 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1216 of the CUBN protein (p.Pro1216Ala). This variant is present in population databases (rs145881708, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with CUBN-related conditions. ClinVar contains an entry for this variant (Variation ID: 648851). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CUBN 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.
GeneDx RCV001759533 SCV002007310 uncertain significance not provided 2019-12-31 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Fulgent Genetics, Fulgent Genetics RCV002501081 SCV002776451 uncertain significance Imerslund-Grasbeck syndrome type 1; Proteinuria, chronic benign 2022-05-12 criteria provided, single submitter clinical testing
Ambry Genetics RCV002534760 SCV003556840 uncertain significance Inborn genetic diseases 2021-12-07 criteria provided, single submitter clinical testing The c.3646C>G (p.P1216A) alteration is located in exon 25 (coding exon 25) of the CUBN gene. This alteration results from a C to G substitution at nucleotide position 3646, causing the proline (P) at amino acid position 1216 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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