Submissions for variant NM_001081.4(CUBN):c.1349G>A (p.Gly450Asp)

gnomAD frequency: 0.00034  dbSNP: rs146463364

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000756007	SCV000883702	uncertain significance	not provided	2017-09-08	criteria provided, single submitter	clinical testing	The c.1349G>A; p.Gly450Asp variant (rs146463364) has not been reported in the medical literature, nor has it been previously identified by our laboratory. This variant is listed in the Genome Aggregation Database (gnomAD) with a population frequency of 0.1 percent in the African population (identified on 33 out of 24,030 chromosomes). The glycine at position 450 is moderately conserved across 10 species (Alamut v2.9.0) and computational analyses of the effects of the p.Gly450Asp variant on protein structure and function provide conflicting results (SIFT: tolerated, MutationTaster: disease causing, PolyPhen-2: benign). Altogether, there is not enough evidence to classify the p.Gly450Asp variant with certainty.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001855868	SCV002130843	uncertain significance	Imerslund-Grasbeck syndrome	2023-11-28	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 450 of the CUBN protein (p.Gly450Asp). This variant is present in population databases (rs146463364, gnomAD 0.1%). 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: 618058). 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	RCV000756007	SCV005421476	uncertain significance	not provided	2024-06-07	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Fulgent Genetics, Fulgent Genetics	RCV005036081	SCV005670964	uncertain significance	Imerslund-Grasbeck syndrome type 1; Proteinuria, chronic benign	2024-05-28	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004742626	SCV005349719	uncertain significance	CUBN-related disorder	2024-05-03	no assertion criteria provided	clinical testing	The CUBN c.1349G>A variant is predicted to result in the amino acid substitution p.Gly450Asp. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.14% of alleles in individuals of African descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.