VCV002444243.3 - ClinVar

NM_001033.5(RRM1):c.1142G>A (p.Arg381His)

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.

(2)

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.

Uncertain significance

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001033.5(RRM1):c.1142G>A (p.Arg381His)

Variation ID: 2444243 Accession: VCV002444243.3

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p15.4 11: 4123206 (GRCh38) [ NCBI UCSC ] 11: 4144436 (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 18, 2023	Dec 17, 2023	Feb 23, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001033.5:c.1142G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001024.1:p.Arg381His	missense
NM_001318064.1:c.851G>A	NP_001304993.1:p.Arg284His	missense
NM_001318065.1:c.128G>A	NP_001304994.1:p.Arg43His	missense
NM_001330193.1:c.476G>A	NP_001317122.1:p.Arg159His	missense
NC_000011.10:g.4123206G>A
NC_000011.9:g.4144436G>A
NG_027992.2:g.33513G>A
LRG_324:g.33513G>A
LRG_324t1:c.1142G>A	LRG_324p1:p.Arg381His

... more HGVS ... less HGVS

Protein change

R159H, R284H, R381H, R43H

Other names

Canonical SPDI

NC_000011.10:4123205: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

OMIM: 180410.0001 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.
RRM1		-	-	GRCh38 GRCh37	33	57

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.
RRM1-related disorder	Uncertain significance (1)	criteria provided, single submitter	Feb 23, 2023	RCV003153041.1
Progressive external ophthalmoplegia with mitochondrial dna deletions, autosomal recessive 6	Pathogenic (1)	no assertion criteria provided	Dec 7, 2023	RCV003447337.2

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.
Uncertain significance (Feb 23, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	RRM1-related disorder Affected status: yes Allele origin: unknown	3billion Accession: SCV003841755.1 First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023	Comment: The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest no damaging effect of the variant on gene or gene … (more) The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest no damaging effect of the variant on gene or gene product (REVEL: 0.26; 3Cnet: 0.01). Therefore, this variant is classified as VUS according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Abdominal distention (present) , Abdominal pain (present) , Gastrointestinal dysmotility (present) , Small intestinal dysmotility (present) , Malabsorption (present) , Inborn mitochondrial myopathy (present)
Pathogenic (Dec 07, 2023)	no assertion criteria provided Method: literature only	PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA, AUTOSOMAL RECESSIVE 6 Affected status: not provided Allele origin: germline	OMIM Accession: SCV004174823.2 First in ClinVar: Dec 09, 2023 Last updated: Dec 17, 2023	Publications: Shintaku, J., Pernice, W. M., (more...) Shintaku, J., Pernice, W. M., Eyaid, W., Gc, J. B., Brown, Z. P., Juanola-Falgarona, M., Torres-Torronteras, J., Sommerville, E. W., Hellebrekers, D. M., Blakely, E. L., Donaldson, A., van de Laar, I., and 12 others RRM1 variants cause a mitochondrial DNA maintenance disorder via impaired de novo nucleotide synthesis. J. Clin. Invest. 132: e145660, 2022. Comment on evidence: In 2 patients (patients 1a and 1b) from a consanguineous Saudi Arabian family with autosomal recessive progressive external ophthalmoplegia-6 (PEOB6; 620647), Shintaku et al. (2022) … (more) In 2 patients (patients 1a and 1b) from a consanguineous Saudi Arabian family with autosomal recessive progressive external ophthalmoplegia-6 (PEOB6; 620647), Shintaku et al. (2022) identified homozygosity for a c.1142G-A transition (c.1142G-A, NM_001033.5) in the RRM1 gene, resulting in an arg381-to-his (R381H) substitution. The mutation, which was identified by whole-exome sequencing, segregated with disease in the family. The mutation was not present in the gnomAD database (v2.1.1). Ribonucleotide reductase activity was reduced in fibroblasts from the patients, and mtDNA was reduced in proliferating fibroblasts from the patients. (less)

Citation text

Shintaku, J., Pernice, W. M., Eyaid, W., Gc, J. B., Brown, Z. P., Juanola-Falgarona, M., Torres-Torronteras, J., Sommerville, E. W., Hellebrekers, D. M., Blakely, E. L., Donaldson, A., van de Laar, I., and 12 others RRM1 variants cause a mitochondrial DNA maintenance disorder via impaired de novo nucleotide synthesis. J. Clin. Invest. 132: e145660, 2022.

Comment:

The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest no damaging effect of the variant on gene or gene product (REVEL: 0.26; 3Cnet: 0.01). Therefore, this variant is classified as VUS according to the recommendation of ACMG/AMP guideline.

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
RRM1 variants cause a mitochondrial DNA maintenance disorder via impaired de novo nucleotide synthesis.	Shintaku J	The Journal of clinical investigation	2022	PMID: 35617047

Text-mined citations for this variant ...

Record last updated Jun 23, 2024

ClinVar Genomic variation as it relates to human health

NM_001033.5(RRM1):c.1142G>A (p.Arg381His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...