ClinVar Genomic variation as it relates to human health
NM_006397.3(RNASEH2A):c.69G>A (p.Val23=)
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_006397.3(RNASEH2A):c.69G>A (p.Val23=)
Variation ID: 66067 Accession: VCV000066067.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.13 19: 12806742 (GRCh38) [ NCBI UCSC ] 19: 12917556 (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 Nov 24, 2016 Feb 14, 2024 Dec 26, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_006397.3:c.69G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_006388.2:p.Val23= synonymous NC_000019.10:g.12806742G>A NC_000019.9:g.12917556G>A NG_012662.1:g.5129G>A NG_029901.1:g.139C>T NG_068122.1:g.1012G>A LRG_278:g.5129G>A LRG_278t1:c.69G>A LRG_278p1:p.Val23= - Protein change
- Other names
- V23V
- Canonical SPDI
- NC_000019.10:12806741:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- cryptic splice donor activation Variation Ontology [VariO:0374]
- PubMed: 23592335
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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.
Exome Aggregation Consortium (ExAC) 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
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
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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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LOC117038795 | - | - | - | GRCh38 | - | 77 |
RNASEH2A | - | - |
GRCh38 GRCh37 |
422 | 515 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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 (4) |
criteria provided, multiple submitters, no conflicts
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Dec 26, 2023 | RCV000056304.20 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Sep 9, 2021 | RCV001731349.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 10, 2022 | RCV002307387.9 |
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
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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
(Dec 26, 2023)
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criteria provided, single submitter
Method: clinical testing
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Aicardi-Goutieres syndrome 4
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002285682.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change affects codon 23 of the RNASEH2A mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid … (more)
This sequence change affects codon 23 of the RNASEH2A mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the RNASEH2A protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs397515480, gnomAD 0.004%). This variant has been observed in individuals with Aicardi-Goutieres syndrome (PMID: 23592335). ClinVar contains an entry for this variant (Variation ID: 66067). Studies have shown that this variant results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 23592335). The resulting mRNA is expected to undergo nonsense-mediated decay. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
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Likely pathogenic
(Sep 09, 2021)
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criteria provided, single submitter
Method: clinical testing
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Aicardi Goutieres syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001983609.1
First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021 |
Comment:
Variant summary: RNASEH2A c.69G>A alters a non-conserved nucleotide resulting in a synonymous change. Several computational tools predict a significant impact on normal splicing: four predict … (more)
Variant summary: RNASEH2A c.69G>A alters a non-conserved nucleotide resulting in a synonymous change. Several computational tools predict a significant impact on normal splicing: four predict the variant creates a 5' donor site. At least one publication reported experimental evidence and demonstrated that in patient derived cells this variant variant resulted in altered mRNA splicing, causing an out of frame deletion, with the insertion of 20 amino acids followed by a premature stop codon at amino acid 42 (Rice_2013). The variant allele was found at a frequency of 1.7e-05 in 180420 control chromosomes (gnomAD). c.69G>A has been reported in the literature in at least three compound heterozygous individuals affected with Aicardi Goutieres Syndrome (Rice_2013, Crow_2015 and LOVD). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, and reported reduction of all three RNase H2 subunits and strongly reduced enzyme activity from patient derived cells (Rice_2013). One submitter have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Pathogenic
(May 06, 2021)
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criteria provided, single submitter
Method: clinical testing
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Aicardi-Goutieres syndrome 4
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002768033.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Aicardi-Goutieres syndrome 4 (MIM#610333). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. Analysis of patient cells by RT-PCR shows this variant results in the formation of a donor splice site within exon 1, leading to an out-of-frame shift in the reading frame and the formation of a protein predicted to undergo nonsense-mediated decay (NMD) (p.(Val23Alafs*21)) (PMID: 23592335). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (3 heterozygotes, 0 homozygotes). (SP) 0703 - Other NMD-predicted variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. These variants have been reported in several patients with Aicardi-Goutieres syndrome (ClinVar, PMID: 25604658). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been described as pathogenic, and reported in at least three unrelated families with Aicardi-Goutieres syndrome (ClinVar, PMID: 25604658, PMID: 23592335, PMID: 31130681). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Transfected lymphoblastoid cell lines have shown this variant resulted in significantly reduced enzyme activity (PMID: 23592335). (SP) 1101 - Very strong and specific phenotype match for this individual. (SP) 1205 - This variant has been shown to be maternally inherited (LABID). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Nov 10, 2022)
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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: SCV002601209.2
First in ClinVar: Nov 19, 2022 Last updated: Mar 04, 2023 |
Comment:
RT-PCR analysis demonstrated that the c.69 G>A variant forms a new splice donor site resulting in an out-of-frame deletion at the end of exon 1 … (more)
RT-PCR analysis demonstrated that the c.69 G>A variant forms a new splice donor site resulting in an out-of-frame deletion at the end of exon 1 leading to a premature termination codon at amino acid 42; This variant is associated with the following publications: (PMID: 17846997, 21454563, 23592335, 25604658, 31130681) (less)
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Pathogenic
(May 13, 2011)
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no assertion criteria provided
Method: literature only
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AICARDI-GOUTIERES SYNDROME 4
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000087473.3
First in ClinVar: Oct 14, 2013 Last updated: Sep 17, 2018 |
Comment on evidence:
In an Italian boy with Aicardi-Goutieres syndrome-4 (AGS4; 610333) who died at 3.5 years of age, Rice et al. (2013) identified compound heterozygosity for 2 … (more)
In an Italian boy with Aicardi-Goutieres syndrome-4 (AGS4; 610333) who died at 3.5 years of age, Rice et al. (2013) identified compound heterozygosity for 2 mutations in the RNASEH2A gene. The first mutation was a c.69G-A transition in exon 1, resulting in a val23-to-val (V23V) substitution and predicted to create a new donor splice site; sequencing confirmed an out-of-frame deletion and insertion of 20 amino acids followed by a premature stop codon at residue 42. The second mutation was a c.556C-T transition in exon 6, resulting in an arg186-to-trp (R186W; 606034.0005) substitution at a highly conserved residue. His unaffected parents were each heterozygous for 1 of the mutations. Coffin et al. (2011) performed kinetic analysis of wildtype and R186W mutant RNASEH2A and observed that the mutant showed dramatically reduced activity, measured at 1/160, 1/9, and 1/8 relative to wildtype, as well as reduced binding affinity, measured at 1/8, 1/25, and 1/100 relative to wildtype, using polynucleotide substrates containing 1, 4, and 20 ribonucleotides, respectively. Catalytic efficiency with the R186W mutant was 1/56 of the efficiency of the wildtype protein. (less)
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not provided
(-)
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no classification provided
Method: literature only
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Aicardi-Goutieres syndrome 4
Affected status: yes
Allele origin:
germline
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GeneReviews
Accession: SCV000147912.4
First in ClinVar: Apr 19, 2014 Last updated: Oct 01, 2022 |
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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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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. | Adam MP | - | 2016 | PMID: 20301648 |
Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1. | Crow YJ | American journal of medical genetics. Part A | 2015 | PMID: 25604658 |
Synonymous mutations in RNASEH2A create cryptic splice sites impairing RNase H2 enzyme function in Aicardi-Goutières syndrome. | Rice GI | Human mutation | 2013 | PMID: 23592335 |
Functional consequences of the RNase H2A subunit mutations that cause Aicardi-Goutieres syndrome. | Coffin SR | The Journal of biological chemistry | 2011 | PMID: 21454563 |
Clinical and molecular phenotype of Aicardi-Goutieres syndrome. | Rice G | American journal of human genetics | 2007 | PMID: 17846997 |
Text-mined citations for rs397515480 ...
HelpRecord last updated May 01, 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.