ClinVar Miner

Submissions for variant NM_001081.3(CUBN):c.2594G>A (p.Ser865Asn) (rs138083522)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001705401 SCV000321528 benign not provided 2021-01-29 criteria provided, single submitter clinical testing Previously reported as either a pathogenic variant associated with inherited cobalamin (vitamin B12) malabsorption, or in linkage disequilibrium with an undetected CUBN pathogenic variant (Tanner et al., 2012); Identified in a patient with methylmalonic acidemia and not considered to be pathogenic (Pupavac et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22929189, 26827111, 31462756, 33111339)
Invitae RCV000534645 SCV000637261 likely benign Imerslund-Gräsbeck syndrome 2019-12-31 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000255679 SCV000859044 likely benign not specified 2018-01-24 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001105418 SCV001262382 benign Imerslund-Gräsbeck syndrome 1 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001287061 SCV001473702 uncertain significance none provided 2019-09-06 criteria provided, single submitter clinical testing The p.Ser865Asn variant (rs138083522) has been reported previously in four patients with suspected cobalamin (vitamin B12) malabsorption (Tanner 2012): Two siblings from Albania were homozygous for this variant, one Turkish individual was compound heterozygous with another variant, p.Ser1250Phe, and one Scottish individual was heterozygous with no second variant identified. The p.Ser865Asp variant (rs138083522) is listed in the genome Aggregation Database (gnomAD) with a European (Non-Finnish) population frequency of 1.2 % (identified in 1480 out of 126,570, including 6 homozygotes). Serine 865 is moderately conserved in 10 species (considering 10 species, Alamut software v2.10.0) and asparagine is present in chicken (UCSC genome database) suggesting this change may be evolutionarily tolerated. Computational analyses of the effects of the p.Ser865Asn variant on protein structure and function predict a neutral effect (SIFT: tolerated, Align-GVGD: C0, PolyPhen-2: benign).Thus, based on the available evidence, clinical significance of this variant cannot be determined with certainty.

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