NM_001081.4(CUBN):c.10233G>A (p.Trp3411Ter) AND Imerslund-Grasbeck syndrome type 1

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Feb 2, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV002272497.3

Allele description [Variation Report for NM_001081.4(CUBN):c.10233G>A (p.Trp3411Ter)]

NM_001081.4(CUBN):c.10233G>A (p.Trp3411Ter)

Gene:

CUBN:cubilin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

10p13

Genomic location:

Preferred name:

NM_001081.4(CUBN):c.10233G>A (p.Trp3411Ter)

HGVS:

NC_000010.11:g.16835143C>T
NG_008967.1:g.299675G>A
NM_001081.4:c.10233G>AMANE SELECT
NP_001072.2:p.Trp3411Ter
LRG_540t1:c.10233G>A
LRG_540:g.299675G>A
NC_000010.10:g.16877142C>T
NM_001081.3:c.10233G>A

Protein change:

W3411*

Links:

dbSNP: rs144484373

NCBI 1000 Genomes Browser:

rs144484373

Molecular consequence:

NM_001081.4:c.10233G>A - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Imerslund-Grasbeck syndrome type 1 (IGS1)
Synonyms:: Megaloblastic anemia 1, Finnish type; Imerslund-Gräsbeck syndrome 1
Identifiers:: MONDO: MONDO:0100156; MedGen: C4016819; OMIM: 261100

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H3078C07-3 NIA Mouse 15K cDNA Clone Set Mus musculus cDNA clone H3078C07 3', mRN...
H3078C07-3 NIA Mouse 15K cDNA Clone Set Mus musculus cDNA clone H3078C07 3', mRNA sequence
gi|40018223|gnl|dbEST|21034651|gb|B 16.2|

Nucleotide
LRG_857t1 (0)
Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002557978	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 2, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 31497480, 31613795, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002557978

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Feb 2, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Profound vitamin D deficiency in four siblings with Imerslund-Grasbeck syndrome with homozygous CUBN mutation.

Ciancio JIR, Furman M, Banka S, Grunewald S.

JIMD Rep. 2019 Sep;49(1):43-47. doi: 10.1002/jmd2.12072.

PubMed [citation]

PMID:: 31497480
PMCID:: PMC6718117

Human C-terminal CUBN variants associate with chronic proteinuria and normal renal function.

Bedin M, Boyer O, Servais A, Li Y, Villoing-Gaudé L, Tête MJ, Cambier A, Hogan J, Baudouin V, Krid S, Bensman A, Lammens F, Louillet F, Ranchin B, Vigneau C, Bouteau I, Isnard-Bagnis C, Mache CJ, Schäfer T, Pape L, Gödel M, Huber TB, et al.

J Clin Invest. 2020 Jan 2;130(1):335-344. doi: 10.1172/JCI129937. Erratum in: J Clin Invest. 2022 Jun 01;132(11):e161852. doi: 10.1172/JCI161852.

PubMed [citation]

PMID:: 31613795
PMCID:: PMC6934218

See all PubMed Citations (3)

Details of each submission

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002557978.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

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 enriched in patients 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) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (4 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported as pathogenic, and observed in many individuals with proteinuria and Imerslund-Grasbeck syndrome (ClinVar, PMID: 31613795, PMID: 31497480). (SP) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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