NM_001081.4(CUBN):c.703C>T (p.Arg235Ter) AND Imerslund-Grasbeck syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: May 5, 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:: RCV001212584.7

Allele description [Variation Report for NM_001081.4(CUBN):c.703C>T (p.Arg235Ter)]

NM_001081.4(CUBN):c.703C>T (p.Arg235Ter)

Genes:

LOC126860871:MED14-independent group 3 enhancer GRCh37_chr10:17157167-17158366 [Gene]
CUBN:cubilin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

10p13

Genomic location:

Preferred name:

NM_001081.4(CUBN):c.703C>T (p.Arg235Ter)

HGVS:

NC_000010.11:g.17115488G>A
NG_008967.1:g.19330C>T
NM_001081.4:c.703C>TMANE SELECT
NP_001072.2:p.Arg235Ter
LRG_540t1:c.703C>T
LRG_540:g.19330C>T
NC_000010.10:g.17157487G>A
NM_001081.3:c.703C>T

Protein change:

R235*

Links:

dbSNP: rs1461982823

NCBI 1000 Genomes Browser:

rs1461982823

Molecular consequence:

NM_001081.4:c.703C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Imerslund-Grasbeck syndrome
Synonyms:: ENTEROCYTE COBALAMIN MALABSORPTION; ENTEROCYTE INTRINSIC FACTOR RECEPTOR, DEFECT OF; PERNICIOUS ANEMIA, JUVENILE, DUE TO SELECTIVE INTESTINAL MALABSORPTION OF VITAMIN B12, WITH PROTEINURIA; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009853; MedGen: C4551825; Orphanet: 35858; OMIM: PS261100

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001384172	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 5, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 15024727, 22929189, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001384172

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(May 5, 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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Genetically heterogeneous selective intestinal malabsorption of vitamin B12: founder effects, consanguinity, and high clinical awareness explain aggregations in Scandinavia and the Middle East.

Tanner SM, Li Z, Bisson R, Acar C, Oner C, Oner R, Cetin M, Abdelaal MA, Ismail EA, Lissens W, Krahe R, Broch H, Gräsbeck R, de la Chapelle A.

Hum Mutat. 2004 Apr;23(4):327-33.

PubMed [citation]

PMID:: 15024727

Inherited cobalamin malabsorption. Mutations in three genes reveal functional and ethnic patterns.

Tanner SM, Sturm AC, Baack EC, Liyanarachchi S, de la Chapelle A.

Orphanet J Rare Dis. 2012 Aug 28;7:56. doi: 10.1186/1750-1172-7-56.

PubMed [citation]

PMID:: 22929189
PMCID:: PMC3462684

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001384172.6

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

Description

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 942574). This variant has not been reported in the literature in individuals affected with CUBN-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg235*) 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).

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

Last Updated: Apr 7, 2025

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