VCV000005391.12 - ClinVar

NM_015713.5(RRM2B):c.979C>T (p.Arg327Ter)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(6)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_015713.5(RRM2B):c.979C>T (p.Arg327Ter)

Variation ID: 5391 Accession: VCV000005391.12

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 8q22.3 8: 102208210 (GRCh38) [ NCBI UCSC ] 8: 103220438 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Mar 24, 2015	Feb 14, 2024	Dec 26, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_015713.5:c.979C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_056528.2:p.Arg327Ter	nonsense
NM_001172477.1:c.1195C>T	NP_001165948.1:p.Arg399Ter	nonsense
NM_001172478.2:c.823C>T	NP_001165949.1:p.Arg275Ter	nonsense
NC_000008.11:g.102208210G>A
NC_000008.10:g.103220438G>A
NG_016617.1:g.35909C>T
LRG_788:g.35909C>T
LRG_788t1:c.1195C>T	LRG_788p1:p.Arg399Ter
LRG_788t2:c.979C>T	LRG_788p2:p.Arg327Ter

... more HGVS ... less HGVS

Protein change

R399*, R275*

Other names

R327*
p.R327*:CGA>TGA

Canonical SPDI

NC_000008.11:102208209:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA117487 OMIM: 604712.0006 dbSNP: rs121918310 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
RRM2B		-	-	GRCh38 GRCh37	334	414

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 5	Pathogenic (3)	criteria provided, single submitter	Feb 23, 2023	RCV000005722.14
RRM2B-related mitochondrial disease	not provided (1)	no classification provided	-	RCV000119016.12
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Dec 26, 2023	RCV000197531.16

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Feb 23, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 5 Affected status: yes Allele origin: unknown	3billion Accession: SCV003841614.1 First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023	Publications: PubMed (1) PubMed: 19664747 Comment: The variant is not observed in the gnomAD v2.1.1 dataset. This variant was predicted to result in a loss or disruption of normal protein function … (more) The variant is not observed in the gnomAD v2.1.1 dataset. This variant was predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by less than 10%. The variant has been reported to co-segregate with the disease in at least 7 similarly affected relatives/individuals in at least two unrelated families (PMID: 19664747). The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000005391 / PMID: 19664747). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Bilateral ptosis (present) , Autoimmune thrombocytopenia (present) , Abnormal circulating lipid concentration (present) , Ophthalmoplegia (present)
Pathogenic (Dec 26, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003440810.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 19664747‚ 23107649 Comment: This sequence change creates a premature translational stop signal (p.Arg327) in the RRM2B gene. While this is not anticipated to result in nonsense mediated decay, … (more) This sequence change creates a premature translational stop signal (p.Arg327) in the RRM2B gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 25 amino acid(s) of the RRM2B protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with autosomal dominant progressive external ophthalmoplegia (PMID: 19664747, 23107649). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5391). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Oct 17, 2019)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000252197.14 First in ClinVar: Oct 11, 2015 Last updated: Apr 17, 2019	Comment: Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 25 amino acids are lost, and other loss-of-function variants have been … (more) Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 25 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 23107649, 19664747, 33144682) (less)
Pathogenic (Aug 01, 2009)	no assertion criteria provided Method: literature only	PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL DOMINANT 5 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000025904.3 First in ClinVar: Apr 04, 2013 Last updated: Jan 02, 2021	Publications: PubMed (1) PubMed: 19664747 Comment on evidence: In affected members of 2 unrelated families with autosomal dominant progressive external ophthalmoplegia-5 (PEOA5; 613077), Tyynismaa et al. (2009) identified a heterozygous 979C-T transition in … (more) In affected members of 2 unrelated families with autosomal dominant progressive external ophthalmoplegia-5 (PEOA5; 613077), Tyynismaa et al. (2009) identified a heterozygous 979C-T transition in the last exon of the RRM2B gene, resulting in an arg327-to-ter (R327X) substitution. The substitution was predicted to result in a protein lacking the last 25 amino acids. One family was North American of European origin, and the second was Hungarian. The mutation was not observed in 380 control European chromosomes, and there was no evidence of a founder effect. The phenotype was characterized by late-onset of mild ophthalmoplegia and mild muscle weakness. Skeletal muscle biopsies showed mtDNA deletions, but normal mtDNA copy numbers. RNA studies showed that the R328X mRNA escaped nonsense-mediated decay, and that the mutant protein was expressed and stable. The findings suggested that the mutant RRM2B protein can compete with wildtype in binding to ribonucleotide reductase, causing a dominant-negative or gain-of-function effect. (less)
not provided (-)	no classification provided Method: phenotyping only	Autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions 5 Affected status: yes Allele origin: unknown	GenomeConnect, ClinGen Accession: SCV001423177.1 First in ClinVar: Jul 19, 2020 Last updated: Jul 19, 2020	Comment: Variant interpretted as Pathogenic and reported on 04-15-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided … (more) Variant interpretted as Pathogenic and reported on 04-15-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less) Clinical Features: Abnormality of eye movement (present) , Abnormality of vision (present) , Myopia (disease) (present) , Hypermetropia (present) , Abnormal retinal morphology (present) , Tinnitus (present) … (more) Abnormality of eye movement (present) , Abnormality of vision (present) , Myopia (disease) (present) , Hypermetropia (present) , Abnormal retinal morphology (present) , Tinnitus (present) , Memory impairment (present) , Depressivity (present) , Abnormality of muscle physiology (present) , Abnormality of the musculature of the limbs (present) , Abnormality of the musculature (present) , Abnormality of the musculature of the pelvis (present) , Abnormal pattern of respiration (present) , Abnormality of esophagus morphology (present) , Abnormality of the intestine (present) , Colon cancer (present) (less) Indication for testing: Diagnostic Age: 40-49 years Sex: male Method: Sanger Sequencing Testing laboratory: GeneDx Date variant was reported to submitter: 2019-04-15 Testing laboratory interpretation: Pathogenic
not provided (-)	no classification provided Method: literature only	RRM2B-related mitochondrial disease Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV000153714.4 First in ClinVar: May 30, 2014 Last updated: Oct 01, 2022	Publications: PubMed (1) PubMed: 24741716 BookShelf: NBK195854 BookShelf: NBK195854

Comment:

The variant is not observed in the gnomAD v2.1.1 dataset. This variant was predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by less than 10%. The variant has been reported to co-segregate with the disease in at least 7 similarly affected relatives/individuals in at least two unrelated families (PMID: 19664747). The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000005391 / PMID: 19664747). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

This sequence change creates a premature translational stop signal (p.Arg327*) in the RRM2B gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 25 amino acid(s) of the RRM2B protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with autosomal dominant progressive external ophthalmoplegia (PMID: 19664747, 23107649). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5391). For these reasons, this variant has been classified as Pathogenic.

Comment:

Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 25 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 23107649, 19664747, 33144682)

Comment:

Variant interpretted as Pathogenic and reported on 04-15-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
RRM2B Mitochondrial DNA Maintenance Defects.	Adam MP	-	2021	PMID: 24741716
Adults with RRM2B-related mitochondrial disease have distinct clinical and molecular characteristics.	Pitceathly RD	Brain : a journal of neurology	2012	PMID: 23107649
A heterozygous truncating mutation in RRM2B causes autosomal-dominant progressive external ophthalmoplegia with multiple mtDNA deletions.	Tyynismaa H	American journal of human genetics	2009	PMID: 19664747

Text-mined citations for rs121918310 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 19, 2024

ClinVar Genomic variation as it relates to human health

NM_015713.5(RRM2B):c.979C>T (p.Arg327Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121918310 ...