ClinVar Miner

Submissions for variant NM_001081.4(CUBN):c.1010C>T (p.Pro337Leu)

gnomAD frequency: 0.00007  dbSNP: rs202153130
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001811645 SCV001471240 likely pathogenic not provided 2020-02-28 criteria provided, single submitter clinical testing The CUBN c.1010C>T; p.Pro337Leu variant (rs202153130) is reported in the literature in multiple individuals affected with a hereditary vitamin B12 deficiency syndrome (Hauck 2008, Tanner 2012). Affected individuals with this variant have each been reported to carry an additional pathogenic variant (Tanner 2012), including one individual with a partial CUBN deletion confirmed in trans to p.Pro337Leu (Hauck 2008). The p.Pro337Leu variant is found in the non-Finnish European population with an overall allele frequency of 0.02% (29/129158 alleles) in the Genome Aggregation Database. The proline at codon 337 is highly conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be likely pathogenic. References: Hauck FH et al. Imerslund-Grasbeck syndrome in a 15-year-old German girl caused by compound heterozygous mutations in CUBN. Eur J Pediatr. 2008 Jun;167(6):671-5. Tanner SM et al. Inherited cobalamin malabsorption. Mutations in three genes reveal functional and ethnic patterns. Orphanet J Rare Dis. 2012 Aug 28;7:56.
MGZ Medical Genetics Center RCV001095371 SCV002580922 likely pathogenic Imerslund-Grasbeck syndrome type 1 2022-07-19 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002489738 SCV002796632 pathogenic Imerslund-Grasbeck syndrome type 1; Proteinuria, chronic benign 2022-03-08 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV002555971 SCV003223429 pathogenic Imerslund-Grasbeck syndrome 2022-03-01 criteria provided, single submitter clinical testing This missense change has been observed in individual(s) with Imerslund-Gräsbeck syndrome (PMID: 17668238, 22929189). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. For these reasons, this variant has been classified as Pathogenic. 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 873110). This variant is present in population databases (rs202153130, gnomAD 0.02%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 337 of the CUBN protein (p.Pro337Leu).
Ambry Genetics RCV004609623 SCV005104767 pathogenic Inborn genetic diseases 2024-06-18 criteria provided, single submitter clinical testing The c.1010C>T (p.P337L) alteration is located in exon 9 (coding exon 9) of the CUBN gene. This alteration results from a C to T substitution at nucleotide position 1010, causing the proline (P) at amino acid position 337 to be replaced by a leucine (L). Based on data from gnomAD, the T allele has an overall frequency of 0.011% (31/282838) total alleles studied. This variant has been identified in conjunction with other CUBN variants in multiple individuals with vitamin B12 deficiency (Hauck, 2008; Tanner, 2012). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
OMIM RCV001095371 SCV001250979 pathogenic Imerslund-Grasbeck syndrome type 1 2020-05-18 no assertion criteria provided literature only
Revvity Omics, Revvity RCV001811645 SCV003828750 uncertain significance not provided 2021-11-29 flagged submission clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.