NM_016302.4(CRBN):c.1255C>T (p.Arg419Ter) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Dec 11, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV001042931.28

Allele description [Variation Report for NM_016302.4(CRBN):c.1255C>T (p.Arg419Ter)]

NM_016302.4(CRBN):c.1255C>T (p.Arg419Ter)

Genes:

CRBN:cereblon [Gene - OMIM - HGNC]
TRNT1:tRNA nucleotidyl transferase 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3p26.2

Genomic location:

Preferred name:

NM_016302.4(CRBN):c.1255C>T (p.Arg419Ter)

HGVS:

NC_000003.12:g.3150939G>A
NG_016864.2:g.33779C>T
NG_041800.2:g.29024G>A
NM_001173482.1:c.1252C>T
NM_001367321.1:c.*433G>A
NM_016302.4:c.1255C>TMANE SELECT
NP_001166953.1:p.Arg418Ter
NP_057386.2:p.Arg419Ter
LRG_1314:g.29024G>A
NC_000003.11:g.3192623G>A
NM_016302.2:c.1255C>T
NM_016302.3:c.1255C>T
NR_159934.1:n.1956G>A
NR_159936.1:n.1762G>A
NR_159937.1:n.2998G>A

Protein change:

R418*; ARG419TER

Links:

OMIM: 609262.0001; dbSNP: rs121918368

NCBI 1000 Genomes Browser:

rs121918368

Molecular consequence:

NM_001367321.1:c.*433G>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NR_159934.1:n.1956G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_159936.1:n.1762G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_159937.1:n.2998G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_001173482.1:c.1252C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_016302.4:c.1255C>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

Clear Turn Off Turn On

Mus musculus PPPDE peptidase domain containing 2, mRNA (cDNA clone IMAGE:4503366...
Mus musculus PPPDE peptidase domain containing 2, mRNA (cDNA clone IMAGE:4503366), partial cds
gi|18380959|gb|BC022097.1|

Nucleotide
K0718C12-3 NIA Mouse Hematopoietic Stem Cell (Lin-/c-Kit-/Sca-1-) cDNA Library (...
K0718C12-3 NIA Mouse Hematopoietic Stem Cell (Lin-/c-Kit-/Sca-1-) cDNA Library (Long) Mus musculus cDNA clone NIA:K0718C12 IMAGE:30075299 3', mRNA sequence
gi|31500296|gnl|dbEST|18579388|gb|B 83.2|

Nucleotide
K0334H03-3 NIA Mouse Osteoblast cDNA Library (Long) Mus musculus cDNA clone NIA:...
K0334H03-3 NIA Mouse Osteoblast cDNA Library (Long) Mus musculus cDNA clone NIA:K0334H03 IMAGE:30057590 3', mRNA sequence
gi|31490401|gnl|dbEST|18569493|gb|B 89.2|

Nucleotide
Sys1 SYS1 Golgi-localized integral membrane protein homolog (S. cerevisiae) [Mus...
Sys1 SYS1 Golgi-localized integral membrane protein homolog (S. cerevisiae) [Mus musculus]
Gene ID:66460

Gene
Atp6v1e1 ATPase, H+ transporting, lysosomal V1 subunit E1 [Mus musculus]
Atp6v1e1 ATPase, H+ transporting, lysosomal V1 subunit E1 [Mus musculus]
Gene ID:11973

Gene

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001206640	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Feb 14, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 23983124, 24993823, 15557513, 28492532
SCV002544755	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Apr 1, 2022)	germline	clinical testing	Citation Link,
SCV005081521	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Dec 11, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001206640

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Feb 14, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV002544755

CeGaT Center for Human Genetics Tuebingen

criteria provided, single submitter

(CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)

Pathogenic
(Apr 1, 2022)

germline

clinical testing

Citation Link,

SCV005081521

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Dec 11, 2023)

germline

clinical testing

Citation Link

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
not provided	germline	yes	3	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A mental retardation-linked nonsense mutation in cereblon is rescued by proteasome inhibition.

Xu G, Jiang X, Jaffrey SR.

J Biol Chem. 2013 Oct 11;288(41):29573-85. doi: 10.1074/jbc.M113.472092. Epub 2013 Aug 27.

PubMed [citation]

PMID:: 23983124
PMCID:: PMC3795255

Functional effects of a pathogenic mutation in Cereblon (CRBN) on the regulation of protein synthesis via the AMPK-mTOR cascade.

Lee KM, Yang SJ, Choi JH, Park CS.

J Biol Chem. 2014 Aug 22;289(34):23343-52. doi: 10.1074/jbc.M113.523423. Epub 2014 Jul 3.

PubMed [citation]

PMID:: 24993823
PMCID:: PMC4156075

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001206640.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

ClinVar contains an entry for this variant (Variation ID: 1821). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects CRBN function (PMID: 23983124, 24993823). 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. This premature translational stop signal has been observed in individual(s) with intellectual disability (PMID: 15557513). It has also been observed to segregate with disease in related individuals. This sequence change creates a premature translational stop signal (p.Arg419*) in the CRBN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 24 amino acid(s) of the CRBN protein. This variant is present in population databases (rs121918368, gnomAD 0.007%).

#	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

From CeGaT Center for Human Genetics Tuebingen, SCV002544755.16

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

#	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		3	not provided	not provided	not provided

From GeneDx, SCV005081521.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Published functional studies demonstrate the variant results in impaired protein function (PMID: 23983124, 24993823); Nonsense variant predicted to result in protein truncation as the last 24 amino acids are lost, although loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 23983124, 24993823, 15557513)

#	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: Oct 26, 2024

ClinVar

Relating variation to medicine