Submissions for variant NM_001081.4(CUBN):c.4838G>T (p.Arg1613Leu)

dbSNP: rs147343635

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003079265	SCV003462440	uncertain significance	Imerslund-Grasbeck syndrome	2024-04-15	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 1613 of the CUBN protein (p.Arg1613Leu). This variant is present in population databases (rs147343635, gnomAD 0.06%). 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: 2152383). 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 with a negative predictive value of 80%. 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	RCV003149048	SCV003836954	uncertain significance	not provided	2024-01-08	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Mayo Clinic Laboratories, Mayo Clinic	RCV003149048	SCV004225214	uncertain significance	not provided	2023-05-03	criteria provided, single submitter	clinical testing	BP4
Ambry Genetics	RCV004614336	SCV005104776	likely benign	Inborn genetic diseases	2024-03-15	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Fulgent Genetics, Fulgent Genetics	RCV005034642	SCV005666319	uncertain significance	Imerslund-Grasbeck syndrome type 1; Proteinuria, chronic benign	2024-05-23	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004744565	SCV005344522	uncertain significance	CUBN-related disorder	2024-04-03	no assertion criteria provided	clinical testing	The CUBN c.4838G>T variant is predicted to result in the amino acid substitution p.Arg1613Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.064% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.