Submissions for variant NM_001081.4(CUBN):c.4669C>T (p.Leu1557Phe)

gnomAD frequency: 0.00064  dbSNP: rs140970422

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000658122	SCV000779893	uncertain significance	not provided	2018-05-18	criteria provided, single submitter	clinical testing	The L1557F variant in the CUBN gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The L1557F variant is observed in 63/25,746 (0.24%) alleles from individuals of non-Finnish European background and 176/277,074 (0.06%) total alleles in large population cohorts, and no individuals have been reported to be homozygous (Lek et al., 2016). The L1557F variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret L1557F as a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001087887	SCV001004264	likely benign	Imerslund-Grasbeck syndrome	2025-01-29	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001105249	SCV001262189	uncertain significance	Imerslund-Grasbeck syndrome type 1	2018-01-13	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Baylor Genetics	RCV001105249	SCV001521872	uncertain significance	Imerslund-Grasbeck syndrome type 1	2019-01-30	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Mayo Clinic Laboratories, Mayo Clinic	RCV000658122	SCV004225215	uncertain significance	not provided	2023-03-20	criteria provided, single submitter	clinical testing	BP4, PM2
PreventionGenetics, part of Exact Sciences	RCV003907922	SCV004725853	likely benign	CUBN-related disorder	2022-12-20	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).