ClinVar Genomic variation as it relates to human health
NM_002936.6(RNASEH1):c.424G>A (p.Val142Ile)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_002936.6(RNASEH1):c.424G>A (p.Val142Ile)
Variation ID: 372197 Accession: VCV000372197.10
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p25.3 2: 3550458 (GRCh38) [ NCBI UCSC ] 2: 3598048 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Jan 9, 2017 Feb 14, 2024 Apr 6, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002936.6:c.424G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002927.2:p.Val142Ile missense NM_001286834.3:c.346G>A NP_001273763.1:p.Val116Ile missense NM_001286837.3:c.73G>A NP_001273766.1:p.Val25Ile missense NM_001378271.1:c.424G>A NP_001365200.1:p.Val142Ile missense NM_001378272.1:c.421G>A NP_001365201.1:p.Val141Ile missense NM_001378273.1:c.424G>A NP_001365202.1:p.Val142Ile missense NR_148532.2:n.497G>A non-coding transcript variant NR_148533.2:n.497G>A non-coding transcript variant NR_148534.2:n.497G>A non-coding transcript variant NR_165465.1:n.381G>A non-coding transcript variant NR_165466.1:n.497G>A non-coding transcript variant NR_165467.1:n.666G>A non-coding transcript variant NR_165468.1:n.469G>A non-coding transcript variant NC_000002.12:g.3550458C>T NC_000002.11:g.3598048C>T NG_051310.1:g.12914G>A LRG_1090:g.12914G>A LRG_1090t1:c.424G>A LRG_1090p1:p.Val142Ile - Protein change
- V142I, V25I, V116I, V141I
- Other names
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- Canonical SPDI
- NC_000002.12:3550457:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00004
Exome Aggregation Consortium (ExAC) 0.00005
Trans-Omics for Precision Medicine (TOPMed) 0.00000
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 | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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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. |
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RNASEH1 | - | - |
GRCh38 GRCh37 |
153 | 206 |
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
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Apr 12, 2021 | RCV000412621.5 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Apr 6, 2022 | RCV001566031.5 |
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. |
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Likely pathogenic
(Apr 12, 2021)
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criteria provided, single submitter
Method: clinical testing
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Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 2
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Centre for Inherited Metabolic Diseases, Karolinska University Hospital
Accession: SCV001571366.1
First in ClinVar: Apr 18, 2021 Last updated: Apr 18, 2021 |
Family history: no
Secondary finding: no
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Pathogenic
(Dec 18, 2019)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001789496.1
First in ClinVar: Aug 19, 2021 Last updated: Aug 19, 2021 |
Comment:
Published functional studies demonstrate that the V142I variant damages the mitochondria and significantly impairs the function of RNASEH1 with approximately 60% decreased activity compared to … (more)
Published functional studies demonstrate that the V142I variant damages the mitochondria and significantly impairs the function of RNASEH1 with approximately 60% decreased activity compared to wild-type (Akman et al., 2016; Reyes et al., 2015); This variant is associated with the following publications: (PMID: 31271879, 31178343, 30340744, 26094573, 28508084, 27402764, 26968897) (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 2
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004100450.1
First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023 |
Comment:
The missense variant p.V142I in RNASEH1 (NM_002936.6) has been previously reported in affected indviduals. Functional studies reveal a damaging effect (Reyes et al,2016). The variant … (more)
The missense variant p.V142I in RNASEH1 (NM_002936.6) has been previously reported in affected indviduals. Functional studies reveal a damaging effect (Reyes et al,2016). The variant has been submitted to ClinVar as Pathogenic. The p.V142I variant is observed in 6/34,588 (0.0173%) alleles from individuals of Latino background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.V142I missense variant is predicted to be damaging by both SIFT and PolyPhen2. The valine residue at codon 142 of RNASEH1 is conserved in all mammalian species. The nucleotide c.424 in RNASEH1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Ptosis (present) , Dysarthria (present) , Dysphagia (present) , Lower limb muscle weakness (present) , Upper limb muscle weakness (present) , Diplopia (present) , Facial … (more)
Ptosis (present) , Dysarthria (present) , Dysphagia (present) , Lower limb muscle weakness (present) , Upper limb muscle weakness (present) , Diplopia (present) , Facial diplegia (present) , Inborn mitochondrial myopathy (present) , Fatigable weakness (present) (less)
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Pathogenic
(Apr 06, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV003513009.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 142 of the RNASEH1 protein (p.Val142Ile). … (more)
This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 142 of the RNASEH1 protein (p.Val142Ile). This variant is present in population databases (rs766294940, gnomAD 0.02%). This missense change has been observed in individuals with chronic progressive external ophthalmoplegia with mitochondrial DNA deletions (PMID: 26094573, 28508084). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 372197). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jul 29, 2015)
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no assertion criteria provided
Method: literature only
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PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL RECESSIVE 2
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000490270.1
First in ClinVar: Jan 09, 2017 Last updated: Jan 09, 2017 |
Comment on evidence:
In a 42-year-old man (S1) with autosomal recessive progressive external ophthalmoplegia with mitochondrial DNA deletions-2 (PEOB2; 616479), Reyes et al. (2015) identified compound heterozygous mutations … (more)
In a 42-year-old man (S1) with autosomal recessive progressive external ophthalmoplegia with mitochondrial DNA deletions-2 (PEOB2; 616479), Reyes et al. (2015) identified compound heterozygous mutations in the RNASEH1 gene: a c.424G-A transition (c.424G-A, NM_002936.4) in exon 4, resulting in a val142-to-ile (V142I) substitution at a highly conserved residue in the catalytic domain, and a c.469C-T transition in exon 4, resulting in an arg157-to-ter (R157X; 604123.0002) substitution in the catalytic domain. The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family and were extremely rare (frequency of less than 0.01%) in the ExAC database. Screening of the RNASEH1 gene in a cohort of 40 genetically undefined patients with a similar disorder identified another unrelated man (S2) who was compound heterozygous for the V142I mutation and a c.554C-T transition in exon 5, resulting in an ala185-to-val (A185V; 604123.0003) substitution at a highly conserved residue in the catalytic domain. A third proband (S3) was homozygous for the V142I mutation. In vitro functional expression assays in E. coli showed that the V142I mutant had about 40% residual activity, the A185V mutant had about 20% residual activity, and the R157X mutant had negligible residual activity, consistent with a loss of function. Skin fibroblasts from patient S1 showed decreased RNASEH1 mRNA transcripts, suggesting nonsense-mediated mRNA decay of the truncating mutation, and virtual absence of the RNASEH1 protein on Western blot analysis, suggesting instability of both variants. Patient cells grew more slowly on galactose medium compared to controls, and had decreased mitochondrial membrane potential as well as abnormal perinuclear aggregation of fragmented mitochondria, suggesting mitochondrial dysfunction. Analysis of mtDNA replication intermediates was consistent with a defect in the removal of RNA, resulting in slower replication. (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Clinicopathologic and molecular spectrum of RNASEH1-related mitochondrial disease. | Bugiardini E | Neurology. Genetics | 2017 | PMID: 28508084 |
RNASEH1 Mutations Impair mtDNA Replication and Cause Adult-Onset Mitochondrial Encephalomyopathy. | Reyes A | American journal of human genetics | 2015 | PMID: 26094573 |
Text-mined citations for rs766294940 ...
HelpRecord last updated Apr 06, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.