Submissions for variant NM_001081.4(CUBN):c.5913_5916del (p.Thr1972fs)

dbSNP: rs765301342

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV004760779	SCV000914451	likely pathogenic	Imerslund-Grasbeck syndrome type 1	2024-09-05	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000778276	SCV000967607	likely pathogenic	Imerslund-Grasbeck syndrome	2019-01-04	criteria provided, single submitter	clinical testing	The p.Thr1972LeufsX10 variant in CUBN has not been previously reported in indivi duals with Imerslund-Grasbeck syndrome or megaloblastic anemia but has been iden tified in 12/128804 of European chromosomes by gnomAD (http://gnomad.broadinstit ute.org). Although this variant has been seen in the general population, its fre quency is low enough to be consistent with a recessive carrier frequency. This v ariant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 1972 and leads to a premature termination codon 10 amino acids downstream. This alteration is then predicted to lead to a trunca ted or absent protein. Loss of function of the CUBN gene is an established disea se mechanism in autosomal recessive Imerslund-Grasbeck syndrome. In summary, alt hough additional studies are required to fully establish its clinical significan ce, this variant is likely pathogenic. ACMG/AMP criteria applied: PVS1, PM2
Revvity Omics, Revvity	RCV001784381	SCV002019776	pathogenic	not provided	2019-09-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000778276	SCV003292195	pathogenic	Imerslund-Grasbeck syndrome	2024-09-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr1972Leufs*10) in the CUBN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CUBN are known to be pathogenic (PMID: 15024727, 22929189, 25349199, 31613795, 34979989). This variant is present in population databases (rs765301342, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with chronic proteinuria (PMID: 31613795). ClinVar contains an entry for this variant (Variation ID: 631629). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001784381	SCV005079346	likely pathogenic	not provided	2023-06-25	criteria provided, single submitter	clinical testing	Reported in the published literature in association with chronic proteinuria (Bedin et al., 2020; Shi et al., 2023); Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 33774617, 30924900, 37312928, 31613795)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004788185	SCV005400404	pathogenic	Proteinuria, chronic benign	2024-10-09	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Imerslund-Grasbeck syndrome 1 (MIM#261100) and chronic benign proteinuria (MIM#618884). Variants downstream of the vitamin B12/IF-binding domain are associated with isolated proteinuria (PMID: 31613795). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 17 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified multiple times as likely pathogenic/pathogenic, and once as a VUS, by clinical laboratories in ClinVar. It has also been reported in the literature, including in two compound heterozygous siblings with isolated chronic proteinuria (PMID: 37312928). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
PreventionGenetics, part of Exact Sciences	RCV003918263	SCV004730266	pathogenic	CUBN-related disorder	2024-02-19	no assertion criteria provided	clinical testing	The CUBN c.5913_5916delTACC variant is predicted to result in a frameshift and premature protein termination (p.Thr1972Leufs*10). This variant has been in an individual with chronic proteinuria (Bedin et al. 2020. PubMed ID: 31613795. Table S2). This variant is reported in 0.0093% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in CUBN are expected to be pathogenic. This variant is interpreted as pathogenic.