This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PM3,PP2,PP3, PP5.
ClinVar Genomic variation as it relates to human health
NM_024570.4(RNASEH2B):c.554T>G (p.Val185Gly)
Germline
Classification
Help
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.
(8)
Help
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.
Conflicting classifications of pathogenicity
Pathogenic(2); Likely pathogenic(2); Uncertain significance(1)
Pathogenic(2); Likely pathogenic(2); Uncertain significance(1)
8
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_024570.4(RNASEH2B):c.554T>G (p.Val185Gly)
Variation ID: 1263 Accession: VCV000001263.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q14.3 13: 50945470 (GRCh38) [ NCBI UCSC ] 13: 51519606 (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 Oct 9, 2016 Apr 6, 2024 Mar 17, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_024570.4:c.554T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_078846.2:p.Val185Gly missense NM_001142279.2:c.554T>G NP_001135751.1:p.Val185Gly missense NC_000013.11:g.50945470T>G NC_000013.10:g.51519606T>G NG_009055.1:g.40715T>G LRG_279:g.40715T>G LRG_279t1:c.554T>G LRG_279p1:p.Val185Gly LRG_279t2:c.554T>G LRG_279p2:p.Val185Gly Q5TBB1:p.Val185Gly - Protein change
- V185G
- Other names
- -
- Canonical SPDI
- NC_000013.11:50945469:T:G
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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
Help
The frequency of the allele represented by this VCV record.
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Trans-Omics for Precision Medicine (TOPMed) 0.00000
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| RNASEH2B | - | - |
GRCh38 GRCh37 |
433 | 552 | |
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. |
|---|---|---|---|---|
| Conflicting interpretations of pathogenicity (6) |
criteria provided, conflicting classifications
|
Mar 17, 2024 | RCV000001325.15 | |
| Pathogenic/Likely pathogenic (2) |
no assertion criteria provided
|
- | RCV001729330.2 |
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. |
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|---|---|---|---|---|---|
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Likely pathogenic
(Mar 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
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Aicardi-Goutieres syndrome 2
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002809943.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
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Pathogenic
(Nov 19, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Aicardi-Goutieres syndrome 2
Affected status: yes
Allele origin:
germline
|
Blueprint Genetics
Accession: SCV001426155.1
First in ClinVar: Aug 02, 2020 Last updated: Aug 02, 2020 |
|
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Likely pathogenic
(Mar 20, 2019)
|
criteria provided, single submitter
Method: clinical testing
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Aicardi-Goutieres syndrome 2
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001368623.2
First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PM3,PP2,PP3, PP5.
|
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Pathogenic
(Jul 28, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Aicardi-Goutieres syndrome 2
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003442144.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 185 of the RNASEH2B protein (p.Val185Gly). … (more)
This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 185 of the RNASEH2B protein (p.Val185Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Aicardi-Goutieres syndrome (PMID: 16845400, 28332073, 29239743, 31130681). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1263). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RNASEH2B protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on RNASEH2B function (PMID: 19015152, 19034401, 30889214, 31529068). For these reasons, this variant has been classified as Pathogenic. (less)
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Uncertain significance
(Mar 17, 2024)
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criteria provided, single submitter
Method: research
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Aicardi-Goutieres syndrome 2
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004805163.2
First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024 |
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Pathogenic
(Aug 01, 2006)
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no assertion criteria provided
Method: literature only
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AICARDI-GOUTIERES SYNDROME 2
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000021475.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 09, 2016 |
Comment on evidence:
In affected members of 2 unrelated Italian families with Aicardi-Goutieres syndrome-2 (AGS2; 610181), Crow et al. (2006) identified a homozygous 554T-G transversion in exon 7 … (more)
In affected members of 2 unrelated Italian families with Aicardi-Goutieres syndrome-2 (AGS2; 610181), Crow et al. (2006) identified a homozygous 554T-G transversion in exon 7 of the RNASEH2B gene, resulting in a val185-to-gly (V185G) substitution. Another family of mixed European Canadian and Hungarian descent was compound heterozygous for the V185G mutation and A177T (610326.0001). (less)
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001979533.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001980274.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
|
Comment:
Comment:
This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 185 of the RNASEH2B protein (p.Val185Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Aicardi-Goutieres syndrome (PMID: 16845400, 28332073, 29239743, 31130681). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1263). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RNASEH2B protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on RNASEH2B function (PMID: 19015152, 19034401, 30889214, 31529068). For these reasons, this variant has been classified as Pathogenic.
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:
This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PM3,PP2,PP3, PP5.
Comment:
This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 185 of the RNASEH2B protein (p.Val185Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Aicardi-Goutieres syndrome (PMID: 16845400, 28332073, 29239743, 31130681). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1263). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RNASEH2B protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on RNASEH2B function (PMID: 19015152, 19034401, 30889214, 31529068). For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Characterization of six recombinant human RNase H2 bearing Aicardi-Goutiéres syndrome causing mutations. | Nishimura T | Journal of biochemistry | 2019 | PMID: 31529068 |
| Molecular Genetics and Interferon Signature in the Italian Aicardi Goutières Syndrome Cohort: Report of 12 New Cases and Literature Review. | Garau J | Journal of clinical medicine | 2019 | PMID: 31130681 |
| Aicardi-Goutières Syndrome associated mutations of RNase H2B impair its interaction with ZMYM3 and the CoREST histone-modifying complex. | Shapson-Coe A | PloS one | 2019 | PMID: 30889214 |
| Phenotypic and Molecular Spectrum of Aicardi-Goutières Syndrome: A Study of 24 Patients. | Al Mutairi F | Pediatric neurology | 2018 | PMID: 29239743 |
| Aicardi-Goutières syndrome: unusual neuro-radiological manifestations. | Abdel-Salam GMH | Metabolic brain disease | 2017 | PMID: 28332073 |
| RNaseH2 mutants that cause Aicardi-Goutieres syndrome are active nucleases. | Perrino FW | Journal of molecular medicine (Berlin, Germany) | 2009 | PMID: 19034401 |
| Contributions of the two accessory subunits, RNASEH2B and RNASEH2C, to the activity and properties of the human RNase H2 complex. | Chon H | Nucleic acids research | 2009 | PMID: 19015152 |
| Mutations in genes encoding ribonuclease H2 subunits cause Aicardi-Goutières syndrome and mimic congenital viral brain infection. | Crow YJ | Nature genetics | 2006 | PMID: 16845400 |
Text-mined citations for rs74555752 ...
HelpThese 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 Sep 29, 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.