Submissions for variant NM_001081.4(CUBN):c.9079G>A (p.Gly3027Arg)

gnomAD frequency: 0.00021  dbSNP: rs150202444

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001102942	SCV001259643	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.
GeneDx	RCV001566674	SCV001790233	uncertain significance	not provided	2021-05-06	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31613795)
Athena Diagnostics	RCV001566674	SCV002817269	uncertain significance	not provided	2020-01-08	criteria provided, single submitter	clinical testing	This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study.
CeGaT Center for Human Genetics Tuebingen	RCV001566674	SCV002821496	uncertain significance	not provided	2022-11-01	criteria provided, single submitter	clinical testing	CUBN: PM2, PM3
Labcorp Genetics (formerly Invitae), Labcorp	RCV000625650	SCV003017386	uncertain significance	Imerslund-Grasbeck syndrome	2023-10-03	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 3027 of the CUBN protein (p.Gly3027Arg). This variant is present in population databases (rs150202444, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of CUBN-related conditions (PMID: 31613795). ClinVar contains an entry for this variant (Variation ID: 522508). 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 expected to disrupt CUBN protein function. 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.
Fulgent Genetics, Fulgent Genetics	RCV005034199	SCV005670754	uncertain significance	Imerslund-Grasbeck syndrome type 1; Proteinuria, chronic benign	2024-06-03	criteria provided, single submitter	clinical testing
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV000625650	SCV000746153	uncertain significance	Imerslund-Grasbeck syndrome	2017-10-09	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003965309	SCV004778486	likely pathogenic	CUBN-related disorder	2024-02-22	no assertion criteria provided	clinical testing	The CUBN c.9079G>A variant is predicted to result in the amino acid substitution p.Gly3027Arg. This variant has been reported along with a second (but different) pathogenic or likely pathogenic variant in individuals with suspected steroid-resistant nephrotic syndrome (SRNS) and Alport syndrome (genetic kidney disease cohort II). One patient (Family 14) was compound heterozygous for a likely pathogenic missense variant, and one patient (Family 22) had a pathogenic frameshift variant with unknown phase (Table S2 of Bedin et al. 2020. PubMed ID: 31613795). In addition, at PreventionGenetics, we have found this variant along with a second (but different) pathogenic truncating variant in two patients referred for nephrotic syndrome and focal segmental glomerulosclerosis (FSGS) testing; In one patient the variants were determined to be in trans through a family study. This variant is reported in 0.036% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In summary, this variant is interpreted as likely pathogenic.