Submissions for variant NM_001081.4(CUBN):c.5069C>T (p.Ala1690Val)

gnomAD frequency: 0.00155  dbSNP: rs141640975

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000323051	SCV000361715	likely benign	Imerslund-Grasbeck syndrome type 1	2018-01-12	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000508050	SCV000603268	uncertain significance	not specified	2016-08-08	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000727792	SCV000855196	uncertain significance	not provided	2017-09-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001088899	SCV001001227	likely benign	Imerslund-Grasbeck syndrome	2025-01-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000727792	SCV001795933	uncertain significance	not provided	2021-10-21	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25349199, 31613795, 30547231, 30220432, 31630189)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000508050	SCV005039677	uncertain significance	not specified	2024-03-20	criteria provided, single submitter	clinical testing	Variant summary: CUBN c.5069C>T (p.Ala1690Val) results in a non-conservative amino acid change located in the CUB domain (IPR000859) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0017 in 250532 control chromosomes in the gnomAD database, including 1 homozygotes. c.5069C>T has been reported in the literature in at-least one individual affected with steroid-resistant nephrotic syndrome (example: Sadowski_ 2015) and others have reported this variant is associated with albuminuria in European population (example: Haas_2018, Ahluwalia_ 2019). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30547231, 30220432, 25349199). ClinVar contains an entry for this variant (Variation ID: 299474). Based on the evidence outlined above, the variant was classified as uncertain significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV000727792	SCV005410955	uncertain significance	not provided	2024-04-12	criteria provided, single submitter	clinical testing	BS1
Fulgent Genetics, Fulgent Genetics	RCV005033866	SCV005666738	uncertain significance	Imerslund-Grasbeck syndrome type 1; Proteinuria, chronic benign	2024-06-24	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003930257	SCV004739725	likely benign	CUBN-related disorder	2022-03-07	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).