NM_152617.4(RNF168):c.493C>T (p.Arg165Ter) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: May 8, 2021
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000578904.4

Allele description [Variation Report for NM_152617.4(RNF168):c.493C>T (p.Arg165Ter)]

NM_152617.4(RNF168):c.493C>T (p.Arg165Ter)

Gene:

RNF168:ring finger protein 168 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3q29

Genomic location:

Preferred name:

NM_152617.4(RNF168):c.493C>T (p.Arg165Ter)

HGVS:

NC_000003.12:g.196487464G>A
NG_023425.1:g.21305C>T
NM_152617.4:c.493C>TMANE SELECT
NP_689830.2:p.Arg165Ter
LRG_185t1:c.493C>T
LRG_185:g.21305C>T
NC_000003.11:g.196214335G>A
NM_152617.3:c.493C>T

Protein change:

R165*

Links:

dbSNP: rs148275050

NCBI 1000 Genomes Browser:

rs148275050

Molecular consequence:

NM_152617.4:c.493C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: CN517202

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000681103	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Apr 4, 2019)	germline	clinical testing	Citation Link,
SCV002247318	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 8, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 19203578, 21394101, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000681103

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely pathogenic
(Apr 4, 2019)

germline

clinical testing

Citation Link,

SCV002247318

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(May 8, 2021)

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
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

The RIDDLE syndrome protein mediates a ubiquitin-dependent signaling cascade at sites of DNA damage.

Stewart GS, Panier S, Townsend K, Al-Hakim AK, Kolas NK, Miller ES, Nakada S, Ylanko J, Olivarius S, Mendez M, Oldreive C, Wildenhain J, Tagliaferro A, Pelletier L, Taubenheim N, Durandy A, Byrd PJ, Stankovic T, Taylor AM, Durocher D.

Cell. 2009 Feb 6;136(3):420-34. doi: 10.1016/j.cell.2008.12.042.

PubMed [citation]

PMID:: 19203578

Homozygous deficiency of ubiquitin-ligase ring-finger protein RNF168 mimics the radiosensitivity syndrome of ataxia-telangiectasia.

Devgan SS, Sanal O, Doil C, Nakamura K, Nahas SA, Pettijohn K, Bartek J, Lukas C, Lukas J, Gatti RA.

Cell Death Differ. 2011 Sep;18(9):1500-6. doi: 10.1038/cdd.2011.18. Epub 2011 Mar 11.

PubMed [citation]

PMID:: 21394101
PMCID:: PMC3178430

See all PubMed Citations (3)

Details of each submission

From GeneDx, SCV000681103.2

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

Description

Nonsense 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; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge

#	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

From Invitae, SCV002247318.2

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

Description

This sequence change creates a premature translational stop signal (p.Arg165*) in the RNF168 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RNF168 are known to be pathogenic (PMID: 19203578, 21394101). This variant is present in population databases (rs148275050, ExAC 0.004%). This variant has not been reported in the literature in individuals with RNF168-related conditions. ClinVar contains an entry for this variant (Variation ID: 489117). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.

#	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: Jul 29, 2023

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