VCV000001262.121 - ClinVar

NM_024570.4(RNASEH2B):c.529G>A (p.Ala177Thr)

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.

(52)

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/Likely 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_024570.4(RNASEH2B):c.529G>A (p.Ala177Thr)

Variation ID: 1262 Accession: VCV000001262.121

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 13q14.3 13: 50945445 (GRCh38) [ NCBI UCSC ] 13: 51519581 (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	Jul 16, 2015	Nov 24, 2024	Apr 24, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_024570.4:c.529G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_078846.2:p.Ala177Thr	missense
NM_001142279.2:c.529G>A	NP_001135751.1:p.Ala177Thr	missense
NC_000013.11:g.50945445G>A
NC_000013.10:g.51519581G>A
NG_009055.1:g.40690G>A
LRG_279:g.40690G>A
LRG_279t1:c.529G>A	LRG_279p1:p.Ala177Thr
LRG_279t2:c.529G>A	LRG_279p2:p.Ala177Thr
	Q5TBB1:p.Ala177Thr

... more HGVS ... less HGVS

Protein change

A177T

Other names

NM_001142279.2(RNASEH2B):c.529G>A(p.Ala177Thr)
NM_024570.3(RNASEH2B):c.529G>A(p.Ala177Thr)

Canonical SPDI

NC_000013.11:50945444: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.

0.00020 (A)

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

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

Exome Aggregation Consortium (ExAC) 0.00131

The Genome Aggregation Database (gnomAD), exomes 0.00140

The Genome Aggregation Database (gnomAD) 0.00141

Trans-Omics for Precision Medicine (TOPMed) 0.00150

Links

ClinGen: CA251724 UniProtKB: Q5TBB1#VAR_027284 OMIM: 610326.0001 dbSNP: rs75184679 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.
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.
Aicardi-Goutieres syndrome 2	Pathogenic/Likely pathogenic (31)	criteria provided, multiple submitters, no conflicts	Mar 29, 2024	RCV000001324.71
not provided	Pathogenic/Likely pathogenic (14)	criteria provided, multiple submitters, no conflicts	Apr 24, 2024	RCV000274058.52
Aicardi Goutieres syndrome	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	May 31, 2022	RCV000343151.18
Cerebral palsy	Pathogenic (1)	no assertion criteria provided	-	RCV001293274.8
Abnormality of the nervous system	Pathogenic (1)	criteria provided, single submitter	Jul 10, 2021	RCV001813931.8
Autism spectrum disorder	Pathogenic (1)	criteria provided, single submitter	Aug 5, 2022	RCV003125824.8
RNASEH2B-related disorder	Pathogenic (1)	no assertion criteria provided	Aug 23, 2024	RCV003415614.6
Inborn genetic diseases	Likely pathogenic (1)	criteria provided, single submitter	Jan 28, 2022	RCV004018532.1

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 (Aug 01, 2018)	criteria provided, single submitter (EGL ClinVar v180209 classification definitions) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000340736.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018	Publications: PubMed (4) PubMed: 16845400‚ 19034401‚ 25243380‚ 25343331 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=RNASEH2B Number of individuals with the variant: 3 Sex: mixed
Pathogenic (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Aicardi-Goutieres syndrome 2 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000894013.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (Jan 01, 2015)	criteria provided, single submitter (ACMG Guidelines, 2007) Method: clinical testing	Aicardi-Goutieres syndrome 2 Affected status: yes Allele origin: inherited	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne Accession: SCV000965776.1 First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019
Likely pathogenic (May 31, 2017)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Aicardi Goutieres syndrome (Autosomal recessive inheritance) Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000540198.3 First in ClinVar: Apr 09, 2017 Last updated: May 03, 2018	Publications: PubMed (11) PubMed: 17846997‚ 19034401‚ 16845400‚ 26903602‚ 26846091‚ 26182405‚ 20131292‚ 25274781‚ 25604658‚ 25243380‚ 25343331 Comment: The p.Ala177Thr variant (NM_024570.3 c.529G>A) in RNASEH2B has been reported in >50 homozygous and 7 compound heterozygous individuals with Aicardi-Goutieres sy ndrome related disorders (progressive … (more) The p.Ala177Thr variant (NM_024570.3 c.529G>A) in RNASEH2B has been reported in >50 homozygous and 7 compound heterozygous individuals with Aicardi-Goutieres sy ndrome related disorders (progressive spastic paraplegia), and segregated with d isease in at least 2 siblings (Rump 2016, Rice 2007, Crow 2006, Crow 2014, La Pi ana 2014, Crow 2015 and Ramatani 2010). Another >50 individuals were heterozygou s for this variant, though it is unclear if they were compound heterozygous for another variant in this gene or not. Although a second variant was not identifie d in a large number of individuals, the allele frequency in cases is statistical ly significantly increased compared to the general population (168/446 from lite rature vs 128/66494 ExAC, p value 0.0001 (Chi-square with Yates correction), sug gesting a causative role. This variant has also been reported in ClinVar (Variat ion ID#1262) as pathogenic by multiple laboratories. In vitro functional studies provide conflicting data ( Lim 2015 and Pizzi 2015). Homozygous mouse models de monstrate phenotypes similar to Aicardi-Goutieres syndrome (Mackenzie 2016). Thi s variant has been identified in 0.19% (128/66494) of European chromosomes by th e Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs75 184679). Although this variant has been seen in the general population, its freq uency is low enough to be consistent with a recessive carrier frequency. In summ ary, although additional studies are required to fully establish its clinical si gnificance, the p.Ala177Thr variant is likely pathogenic for Aicardi-Goutieres s yndrome in an autosomal recessive manner based upon segregation studies, animal models, functional evidence and its occurrence in patients with this disease. (less) Number of individuals with the variant: 2
Pathogenic (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Aicardi-Goutieres syndrome 2 Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001139343.1 First in ClinVar: Jan 10, 2020 Last updated: Jan 10, 2020
Pathogenic (Oct 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Unknown mechanism) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001447813.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Clinical Features: Spasticity (present) Sex: male
Likely pathogenic (Dec 10, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Aicardi-Goutieres syndrome 2 Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001369896.2 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: PP2,PP3,PS3.
Pathogenic (Apr 24, 2020)	criteria provided, single submitter (NYGC Assertion Criteria 2020) Method: clinical testing	Aicardi-Goutieres syndrome 2 (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	New York Genome Center Study: CSER-NYCKidSeq Accession: SCV001480396.1 First in ClinVar: Feb 20, 2021 Last updated: Feb 20, 2021	Clinical Features: Autism (present) , Intellectual disability (present) , Seizure (present) , Delayed speech and language development (present) , Hypotonia (present) Secondary finding: no
Pathogenic (Mar 22, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Aicardi-Goutieres syndrome 2 Affected status: yes Allele origin: germline	3billion Accession: SCV002318806.1 First in ClinVar: Apr 02, 2022 Last updated: Apr 02, 2022	Publications: PubMed (2) PubMed: 16845400‚ 26903602 Comment: The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 16845400). The variant has been reported to be in trans with a … (more) The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 16845400). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 4 similarly affected unrelated individuals (PMID: 16845400)(PM3_VS). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 26903602). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.614>=0.6). The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency:0.0015308). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Abnormal circulating amino acid concentration (present) , Seizure (present) , Global developmental delay (present)
Likely pathogenic (Jul 01, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	AiLife Diagnostics, AiLife Diagnostics Accession: SCV002501985.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022	Publications: PubMed (21) PubMed: 16845400‚ 29239743‚ 29030706‚ 31367981‚ 30609409‚ 25243380‚ 31980526‚ 32404165‚ 25343331‚ 31920009‚ 26182405‚ 26903602‚ 31130284‚ 31529068‚ 19034401‚ 25274781‚ 33258288‚ 30223285‚ 30111349‚ 29691679‚ 32258229 Number of individuals with the variant: 1 Secondary finding: no
Likely pathogenic (Oct 29, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Aicardi-Goutieres syndrome 2 Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002581269.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PM3_VSTR, PP3	Number of individuals with the variant: 1 Sex: female
Pathogenic (Nov 03, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden Accession: SCV002010692.3 First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023
Likely pathogenic (Apr 18, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Aicardi-Goutieres syndrome 2 Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002019058.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Likely pathogenic (Mar 29, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Aicardi-Goutieres syndrome 2 Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004807903.1 First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024
Pathogenic (Mar 09, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005198074.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (Jan 06, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Aicardi-Goutieres syndrome 2 Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005088784.2 First in ClinVar: Aug 04, 2024 Last updated: Aug 25, 2024	Comment: This variant is predicted to be damaging by in-silico missense prediction tools (SIFT and Polyphen2). The variant was previously reported in individuals with Aicardi-Goutieres syndrome … (more) This variant is predicted to be damaging by in-silico missense prediction tools (SIFT and Polyphen2). The variant was previously reported in individuals with Aicardi-Goutieres syndrome in homozygous as well as compound heterozygous state and segregated with the disease [PMID: 16845400, 17846997, 18754903, 26182405, 26846091, 25604658]. Functional studies have shown that this variant affects RNASEH2B function [PMID: 19015152, 19034401, 26903602]. (less)
Pathogenic (Jan 06, 2017)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV000614883.1 First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017	Publications: PubMed (16) PubMed: 16845400‚ 25243380‚ 25343331‚ 26903602‚ 19034401‚ 25274781‚ 21177854‚ 20131292‚ 27009121‚ 25604658‚ 19015152‚ 26846091‚ 19694776‚ 18754903‚ 18069026‚ 22149989
Likely pathogenic (May 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Aicardi-Goutieres syndrome 2 Affected status: unknown Allele origin: unknown	SIB Swiss Institute of Bioinformatics Accession: SCV000803481.1 First in ClinVar: May 26, 2018 Last updated: May 26, 2018	Publications: PubMed (6) PubMed: 16845400‚ 25274781‚ 17846997‚ 20131292‚ 26846091‚ 28762473 Comment: This variant is interpreted as a Likely Pathogenic, for Aicardi-Goutieres syndrome 2, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PM3 => For … (more) This variant is interpreted as a Likely Pathogenic, for Aicardi-Goutieres syndrome 2, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PM3 => For recessive disorders, detected in trans with a pathogenic variant (PMID:16845400). PS3-Moderate => PS3 downgraded in strength to Moderate (PMID:25274781). PS4-Moderate => Recurrent mutation observed in multiple unrelated patients. (PMID:16845400,17846997,20131292,26846091,28762473). (less)
Pathogenic (Nov 15, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Aicardi-Goutieres syndrome 2 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV001132538.1 First in ClinVar: Dec 23, 2019 Last updated: Dec 23, 2019	Comment: The homozygous p.Ala177Thr variant in RNASEH2B was identified by our study in one individual with Aicardi-Goutieres Syndrome. The p.Ala177Thr variant is pathogenic based off of … (more) The homozygous p.Ala177Thr variant in RNASEH2B was identified by our study in one individual with Aicardi-Goutieres Syndrome. The p.Ala177Thr variant is pathogenic based off of multiple reports in ClinVar and the literature. (less) Clinical Features: Spastic paraplegia (present)
Pathogenic (Jul 21, 2020)	criteria provided, single submitter (Classification criteria August 2017) Method: clinical testing	Aicardi-Goutieres syndrome 2 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München Accession: SCV001430042.1 First in ClinVar: Aug 22, 2020 Last updated: Aug 22, 2020	Clinical Features: Patent foramen ovale (present) , Primary hypothyroidism (present) Sex: male Tissue: blood
Likely pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	Laboratoire de Génétique Moléculaire, CHU Bordeaux Accession: SCV001468967.1 First in ClinVar: Jan 17, 2021 Last updated: Jan 17, 2021
Pathogenic (Jul 10, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Abnormality of the nervous system Affected status: yes Allele origin: germline	Kariminejad - Najmabadi Pathology & Genetics Center Accession: SCV001755491.1 First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022
Pathogenic (Jul 27, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Aicardi-Goutieres syndrome 2 Affected status: yes Allele origin: biparental	Centogene AG - the Rare Disease Company Accession: SCV002059737.1 First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022
Pathogenic (Jan 05, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Aicardi-Goutieres syndrome 2 Affected status: yes Allele origin: germline	DASA Accession: SCV002061178.1 First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022	Publications: PubMed (10) PubMed: 29691679‚ 29239743‚ 16845400‚ 17846997‚ 28762473‚ 25274781‚ 19015152‚ 26903602‚ 23165795‚ 25614871 Comment: The c.529G>A;p.(Ala177Thr) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID:1262; PMID: 29691679; 29239743; 16845400; 17846997;28762473) … (more) The c.529G>A;p.(Ala177Thr) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID:1262; PMID: 29691679; 29239743; 16845400; 17846997;28762473) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID:25274781; 19015152, 26903602) - PS3_moderate. The variant is present at low allele frequencies population databases (rs75184679 – gnomAD 0.01452%; ABraOM 0.002989 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Ala177Thr) was detected in trans with a pathogenic variant (PMID: 16845400; 17846997; 28762473) - PM3. The variant co-segregated with disease in multiple affected family members (PMID: 28762473) - PP1. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. (less) Number of individuals with the variant: 2 Sex: female Geographic origin: Brazil;Uruguay
Pathogenic (Apr 16, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Aicardi-Goutieres syndrome 2 Affected status: yes Allele origin: germline	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center Accession: SCV002061858.2 First in ClinVar: Jan 22, 2022 Last updated: Feb 11, 2022	Comment: PM3_Strong, PS3
Pathogenic (Apr 16, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Aicardi-Goutieres syndrome 2 Affected status: unknown Allele origin: germline	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago Accession: SCV002495930.1 First in ClinVar: Apr 02, 2022 Last updated: Apr 02, 2022	Comment: RNASEH2B NM_024570.3 exon 7 p.Ala177Thr (c.529G>A):This variant has been reported in the literature in numerous individuals with Aicardi-Goutieres syndrome (AGS) in the compound heterozygous and … (more) RNASEH2B NM_024570.3 exon 7 p.Ala177Thr (c.529G>A):This variant has been reported in the literature in numerous individuals with Aicardi-Goutieres syndrome (AGS) in the compound heterozygous and homozygous state and is reported to be the most common pathogenic variant associated with this condition (Selected publications: Crow 2006 PMID:16845400, Al-Mutairi 2018 PMID:29239743, Issa 2020 PMID:32404165, Videira 2020 PMID:32258229). This variant is present in 0.2% (40/15278) of Latino alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/13-50945445-G-A?dataset=gnomad_r3). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as Pathogenic or Likely Pathogenic (Variation ID:1262). Evolutionary conservation and computational predictive tools for this variant are unclear. Functional studies, including a knock-in mouse model predict that this variant will impact the protein and result in downstream instability (Lim 2015 PMID:26182405, Pizzi 2015 PMID:25274781, Mackenzie 2016 PMID:26903602). However, these studies may not accurately represent in vivo biological function and at least one study suggests that the ribonuclease H activities from this variant were comparable to WT (Perrino 2009 PMID:19034401). In summary, this variant is classified as pathogenic based on the data above. (less)
Pathogenic (Oct 14, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Aicardi-Goutieres syndrome 2 Affected status: yes Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV002512642.1 First in ClinVar: May 21, 2022 Last updated: May 21, 2022	Comment: ACMG classification criteria: PS3 supporting, PM3 very strong, PP1 strong, PP1 supporting Geographic origin: Brazil
Pathogenic (May 31, 2022)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Aicardi Goutieres syndrome Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002547569.1 First in ClinVar: Jul 17, 2022 Last updated: Jul 17, 2022	Publications: PubMed (4) PubMed: 29239743‚ 33967934‚ 16845400‚ 26903602 Comment: Variant summary: RNASEH2B c.529G>A (p.Ala177Thr) results in a non-conservative amino acid change located in the Ribonuclease H2 subunit B, wHTH domain (IPR019024) of the encoded … (more) Variant summary: RNASEH2B c.529G>A (p.Ala177Thr) results in a non-conservative amino acid change located in the Ribonuclease H2 subunit B, wHTH domain (IPR019024) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0014 in 251300 control chromosomes. c.529G>A has been widely reported in the literature as homozygous and compound heterozygous genotypes in multiple individuals affected with Aicardi Goutieres Syndrome (example, Crow_2006, Beysen_2021). These data indicate that the variant is very likely to be associated with disease. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Mar 17, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: provider interpretation, clinical testing	Aicardi-Goutieres syndrome 2 Affected status: unknown Allele origin: maternal	Geisinger Autism and Developmental Medicine Institute, Geisinger Health System Accession: SCV000804384.2 First in ClinVar: Sep 06, 2018 Last updated: Dec 11, 2022	Comment: This variant was identified in a 5 year old female with profound intellectual disability, arching, irritability, stereotypy, sleep problems, axial hypotonia, lower extremity hypertonia, optic … (more) This variant was identified in a 5 year old female with profound intellectual disability, arching, irritability, stereotypy, sleep problems, axial hypotonia, lower extremity hypertonia, optic nerve hypoplasia, feeding problems, plagiocephaly, slender fingers, and slender big toe. A brain MRI at age 3 months showed some thinning of falx cerebri. This variant has been reported previously in the literature and ClinVar as pathogenic. A second RNASEH2B variant was not identified, adequate sequence coverage was verified and deletion/duplication analysis was also normal. Additional genetic testing, including chromosomal microarray and mitochondrial DNA sequencing and deletion analysis, have not yielded a diagnosis. (less) Observation 1: Clinical Features: Intellectual disability, profound (present) , Irritability (present) , Stereotypy (present) , Sleep disturbance (present) , Central hypotonia (present) , Lower limb hypertonia (present) , Optic … (more) Intellectual disability, profound (present) , Irritability (present) , Stereotypy (present) , Sleep disturbance (present) , Central hypotonia (present) , Lower limb hypertonia (present) , Optic nerve hypoplasia (present) , Feeding difficulties (present) , Plagiocephaly (present) , Slender finger (present) , Slender toe (present) (less) Age: 0-9 years Sex: female Secondary finding: no Testing laboratory: GeneDx Date variant was reported to submitter: 2017-03-17 Testing laboratory interpretation: Pathogenic Observation 2: Number of individuals with the variant: 1 Clinical Features: Intellectual disability, profound (present) , Irritability (present) , Stereotypy (present) , Sleep disturbance (present) , Central hypotonia (present) , Lower limb hypertonia (present) , Optic … (more) Intellectual disability, profound (present) , Irritability (present) , Stereotypy (present) , Sleep disturbance (present) , Central hypotonia (present) , Lower limb hypertonia (present) , Optic nerve hypoplasia (present) , Feeding difficulties (present) , Plagiocephaly (present) , Slender finger (present) , Slender toe (present) (less) Age: 0-9 years Sex: female Testing laboratory: GeneDx Date variant was reported to submitter: 2017-03-17 Testing laboratory interpretation: Pathogenic
Pathogenic (Aug 05, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autism spectrum disorder Affected status: yes Allele origin: paternal	Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine Accession: SCV003804031.1 First in ClinVar: Feb 18, 2023 Last updated: Feb 18, 2023	Sex: male
Pathogenic (Apr 27, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Aicardi-Goutieres syndrome 2 Affected status: yes Allele origin: germline	Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL) Accession: SCV003920813.1 First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023
Pathogenic (Jan 09, 2023)	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020) Method: clinical testing	Aicardi-Goutieres syndrome 2 Affected status: unknown Allele origin: unknown	Illumina Laboratory Services, Illumina Accession: SCV000384595.3 First in ClinVar: Dec 06, 2016 Last updated: Jul 22, 2023	Publications: PubMed (9) PubMed: 18754903‚ 21177854‚ 29239743‚ 26903602‚ 30826161‚ 25604658‚ 25243380‚ 31130681‚ 21177858 Comment: The RNASEH2B c.529G>A (p.Ala177Thr) missense variant results in the substitution of alanine at amino acid position 177 with threonine. Across a selection of the available … (more) The RNASEH2B c.529G>A (p.Ala177Thr) missense variant results in the substitution of alanine at amino acid position 177 with threonine. Across a selection of the available literature, this variant has been reported in at least 22 individuals in a homozygous state and at least 12 individuals in a compound heterozygous state, including a sibling pair (PMID: 25604658; PMID: 29239743; PMID: 31130681; PMID: 30826161; PMID: 18754903). The highest frequency of this allele in the Genome Aggregation Database is 0.002618 in the Latino/Admixed American population (version 3.1.2). This frequency is consistent with the fact that it is the mostly commonly identified variant in individuals with Aicardi-Goutieres syndrome (PMID: 25243380; PMID: 31130681). Structural and functional studies, including in patient fibroblasts and mouse embryonic fibroblasts from an orthologous knock-in model, have demonstrated that the p.Ala177Thr substitution reduces RNase H2 subunit expression, disrupts the interaction interface of RNASEH2B with RNASEH2C, impairs complex stability, and reduces cellular RNase H2 activity (PMID: 26903602; PMID: 21177858; PMID: 21177854). Homozygous knock-in mice also recapitulate the interferon-stimulated gene signature observed in human patients with Aicardi-Goutieres syndrome. Based on the available evidence, the c.529G>A (p.Ala177Thr) variant is classified as pathogenic for Aicardi-Goutieres syndrome. (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Aicardi-Goutieres syndrome 2 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV004171884.1 First in ClinVar: Dec 09, 2023 Last updated: Dec 09, 2023
Pathogenic (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Aicardi-Goutieres syndrome 2 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000652369.8 First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024	Publications: PubMed (14) PubMed: 28492532‚ 16845400‚ 17846997‚ 18754903‚ 19694776‚ 20131292‚ 25243380‚ 25343331‚ 25604658‚ 26182405‚ 26846091‚ 19015152‚ 19034401‚ 26903602 Comment: This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 177 of the RNASEH2B protein (p.Ala177Thr). … (more) This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 177 of the RNASEH2B protein (p.Ala177Thr). This variant is present in population databases (rs75184679, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Aicardi-Gouti√®res syndrome, and unspecified neurological disorders (PMID: 16845400, 17846997, 18754903, 19694776, 20131292, 25243380, 25343331, 25604658, 26182405, 26846091). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1262). 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 have shown that this missense change affects RNASEH2B function (PMID: 19015152, 19034401, 26903602). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Feb 20, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Aicardi-Goutieres syndrome 2 (Autosomal recessive inheritance) Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001429537.2 First in ClinVar: Aug 15, 2020 Last updated: Mar 10, 2024	Comment: Criteria applied: PM3_VSTR,PS3_MOD Clinical Features: Abnormality of the face (present) , Microcephaly (present) , Seizure (present) , Hearing impairment (present) , Spasticity (present) , Short stature (present) , Intellectual disability, … (more) Abnormality of the face (present) , Microcephaly (present) , Seizure (present) , Hearing impairment (present) , Spasticity (present) , Short stature (present) , Intellectual disability, moderate (present) (less) Sex: male
Likely pathogenic (Jan 28, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV005015109.1 First in ClinVar: May 01, 2024 Last updated: May 01, 2024	Publications: PubMed (4) PubMed: 17846997‚ 25604658‚ 32258229‚ 33967934 Comment: The c.529G>A (p.A177T) alteration is located in exon 7 (coding exon 7) of the RNASEH2B gene. This alteration results from a G to A substitution … (more) The c.529G>A (p.A177T) alteration is located in exon 7 (coding exon 7) of the RNASEH2B gene. This alteration results from a G to A substitution at nucleotide position 529, causing the alanine (A) at amino acid position 177 to be replaced by a threonine (T). Based on data from gnomAD, the A allele has an overall frequency of 0.14% (386/282704) total alleles studied. The highest observed frequency was 0.22% (290/129040) of European (non-Finnish) alleles. This variant has been identified in multiple homozygous individuals with Aicardi-Goutières Syndrome (Rice, 2007; Crow, 2015; Videira, 2020; Beysen, 2021). This amino acid position is not well conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic. (less)
Pathogenic (Nov 08, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Aicardi-Goutieres syndrome 2 Affected status: yes Allele origin: germline	Clinical Genomics Laboratory, Washington University in St. Louis Accession: SCV005045054.1 First in ClinVar: May 26, 2024 Last updated: May 26, 2024	Comment: The RNASEH2B c.529G>A (p.Ala177Thr) variant has been reported in the homozygous and compound heterozygous state in many individuals affected with AGS and related disorders (Beysen … (more) The RNASEH2B c.529G>A (p.Ala177Thr) variant has been reported in the homozygous and compound heterozygous state in many individuals affected with AGS and related disorders (Beysen D et al., PMID: 33967934; Crow YJ et al., PMID: 16845400; Lambe J et al., PMID: 31920009; Pizzi S et al., PMID: 25274781; Rice G et al., PMID: 17846997; Videira G et al., PMID: 32258229). In at least three families, affected individuals who were homozygous for this variant showed marked intrafamilial and interfamilial phenotypic variability (Videira G et al., PMID: 32258229). This variant has been reported in the ClinVar database as a germline pathogenic or likely pathogenic variant in by several submitters. The highest population minor allele frequency in the population database genome aggregation database (v.2.1.1) is 0.2% in the European (non-Finnish) population which is compatible with carrier status for AGS and consistent with this variant being the most commonly identified causative variant (Rice G et al., PMID: 17846997). While computational predictors are uncertain as to the impact of this variant on the RNASEH2B protein, functional studies have shown a modest alteration of enzymatic activity and homozygous knock-in mice recapitulate the interferon-stimulated gene signature observed in human patients with AGS (Chon H et al., PMID: 19015152; Mackenzie KJ et al., PMID: 26903602; Perrino FW et al., PMID: 19034401; Pizzi S et al., PMID: 25274781). Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic. (less)
Pathogenic (Jul 17, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Aicardi-Goutieres syndrome 2 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002767048.2 First in ClinVar: Dec 24, 2022 Last updated: Jul 23, 2024	Publications: PubMed (1) PubMed: 32258229 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 2 (MIM#610181). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Severity varies among patients (OMIM, PMID: 32258229). (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to threonine. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2 & v3: 570 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated RNase H2 complex component wHTH domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as likely pathogenic and pathogenic in multiple individuals (ClinVar) and as homozygous in five patients from three families with differing presentations of Aicardi-Goutieres syndrome (PMID: 32258229). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
Pathogenic (Jan 23, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000329498.12 First in ClinVar: Dec 06, 2016 Last updated: Sep 16, 2024	Comment: Lymphoblastoid cells derived from a patient who harbored the A177T variant showed a destabilizing effect on the RNase H2 protein; however, it is unclear if … (more) Lymphoblastoid cells derived from a patient who harbored the A177T variant showed a destabilizing effect on the RNase H2 protein; however, it is unclear if this perturbation is solely due to the effect of the A177T variant (PMID: 25274781); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis supports that this missense variant does not alter protein structure/function; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: no PMID, 33177673, 34490615, 33872687, 34758253, 31980526, 16845400, 19034401, 26903602, 21177854, 25604658, 27539236, 25343331, 26182405, 33967934, 33307271, 29030706, 29691679, 29239743, 30609409, 30223285, 30111349, 31367981, 31529068, 31920009, 31130284, 32258229, 32404165, 34573280, 25500883, 34426522, 31589614, 33258288, 32342562, 27943079, 34042169, 25274781, 25243380) (less)
Pathogenic (Feb 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001247787.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Comment: RNASEH2B: PM3:Very Strong, PM2, PS3:Supporting Number of individuals with the variant: 15
Pathogenic (Apr 24, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV005414174.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (12) PubMed: 16845400‚ 25274781‚ 25343331‚ 25500883‚ 26903602‚ 31529068‚ 31920009‚ 32258229‚ 33307271‚ 34042169‚ 36775013‚ 37296061 Comment: PM3_very_strong, PS3, PS4_moderate Number of individuals with the variant: 3
Pathogenic (-)	no assertion criteria provided Method: clinical testing	Aicardi-Goutieres syndrome 2 Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV000733351.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018
Pathogenic (Jan 26, 2017)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes Accession: SCV000778237.1 First in ClinVar: Jun 02, 2018 Last updated: Jun 02, 2018
Pathogenic (Dec 05, 2019)	no assertion criteria provided Method: clinical testing	Aicardi-Goutieres syndrome 2 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Clinical Genomics Laboratory, Stanford Medicine Accession: SCV001427209.1 First in ClinVar: Aug 22, 2020 Last updated: Aug 22, 2020	Comment: The p.Ala177Thr variant in the RNASEH2B gene has been previously reported in >20 unrelated individuals with Aicardi-GoutiÃ¨res syndrome (Garau et al., 2019). All individuals were … (more) The p.Ala177Thr variant in the RNASEH2B gene has been previously reported in >20 unrelated individuals with Aicardi-GoutiÃ¨res syndrome (Garau et al., 2019). All individuals were homozygous or compound heterozygous. This variant has also been identified in 290/129,040 European (non-Finnish) chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Well-established in vivo and in vitro functional studies of the p.Ala177Thr variant strongly suggest a deleterious effect to the protein that is sufficient to be disease-causing (Mackenzie et al., 2016; Pizzi et al., 2014). These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Ala177Thr variant as pathogenic for autosomal recessive Aicardi-GoutiÃ¨res syndrome based on the information above. [ACMG evidence codes used: PS3; PM3_Strong (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	Cerebral palsy (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Centre of Medical Genetics, University of Antwerp Accession: SCV001481865.1 First in ClinVar: Feb 28, 2021 Last updated: Feb 28, 2021	Publications: PubMed (2) PubMed: 28762473‚ 32258229 Comment: missense mutation, previously described as pathogenic in the literature and in ClinVar Observation 1: Clinical Features: Spastic diplegia (present) , Lower limb hypertonia (present) , Recurrent fever (present) , Periventricular cysts (present) , Lower limb hyperreflexia (present) Age: 0-9 years Sex: female Observation 2: Clinical Features: Intellectual disability, mild (present) , Tetraplegia (present) , Delayed speech and language development (present) , Chilblains (present) , Abnormal corpus callosum morphology (present) , Scoliosis … (more) Intellectual disability, mild (present) , Tetraplegia (present) , Delayed speech and language development (present) , Chilblains (present) , Abnormal corpus callosum morphology (present) , Scoliosis (present) , Flexion contracture (present) (less) Age: 10-19 years Sex: female
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, Amsterdam University Medical Center Study: VKGL Data-share Consensus Accession: SCV001809098.1 First in ClinVar: Aug 27, 2021 Last updated: Aug 27, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	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: SCV001967818.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021
Pathogenic (Aug 23, 2024)	no assertion criteria provided Method: clinical testing	RNASEH2B-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004106595.2 First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024	Comment: The RNASEH2B c.529G>A variant is predicted to result in the amino acid substitution p.Ala177Thr. This is the most common causative variant in the RNASEH2B gene. … (more) The RNASEH2B c.529G>A variant is predicted to result in the amino acid substitution p.Ala177Thr. This is the most common causative variant in the RNASEH2B gene. The c.529G>A variant has been observed in over twenty unrelated families to be causative for Aicardi-Goutiéres syndrome and in two families with uncomplicated spastic paraplegia (Crow et al. 2006. PubMed ID: 16845400; Crow et al. 2014. PubMed ID: 25243380; Rice et al. 2007. PubMed ID: 17846997). Functional studies have shown that this variant destabilizes the RNase H2 protein complex (Pizzi et al. 2015. PubMed ID: 25274781). In summary, we classify this variant as pathogenic. (less)
Pathogenic (Dec 01, 2014)	no assertion criteria provided Method: literature only	AICARDI-GOUTIERES SYNDROME 2 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000021474.3 First in ClinVar: Apr 04, 2013 Last updated: Jul 16, 2015	Publications: PubMed (2) PubMed: 16845400‚ 25243380 Comment on evidence: In affected members of 7 families with Aicardi-Goutieres syndrome-2 (AGS2; 610181), Crow et al. (2006) identified a homozygous 529G-A transition in exon 7 of the … (more) In affected members of 7 families with Aicardi-Goutieres syndrome-2 (AGS2; 610181), Crow et al. (2006) identified a homozygous 529G-A transition in exon 7 of the RNASEH2B gene, resulting in an ala177-to-thr (A177T) substitution. The families were of distinct nationality (Algerian, Moroccan, Irish, Italian, French Canadian, and German). Seven additional families were compound heterozygous for the A177T mutation and a different pathogenic mutation in the RNASEH2B gene (see, e.g., 610326.0002). In total, 20 of the 36 mutant alleles in 18 AGS families were A177T. In 2 Egyptian sibs and an unrelated patient of North African descent who presented with nonsyndromic spastic paraplegia around age 2 years following normal psychomotor development, Crow et al. (2014) identified a homozygous A177T mutation in the RNASEH2B gene. The mutation was found by exome sequencing and confirmed by Sanger sequencing. None of the patients had increased interferon levels. Crow et al. (2014) emphasized the phenotypic variability associated with AGS, noting that neurologic dysfunction is not always marked in this disorder. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	Aicardi-Goutieres syndrome 2 (Autosomal recessive inheritance) Affected status: yes Allele origin: inherited	Génétique des Maladies du Développement, Hospices Civils de Lyon Accession: SCV001623555.1 First in ClinVar: May 23, 2021 Last updated: May 23, 2021
Pathogenic (-)	no assertion criteria provided (ACGS Guidelines, 2016) Method: clinical testing	Aicardi-Goutieres syndrome 2 Affected status: yes Allele origin: germline	Genomics England Pilot Project, Genomics England Accession: SCV001760322.1 First in ClinVar: Jul 31, 2021 Last updated: Jul 31, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001932543.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
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Comment:

The p.Ala177Thr variant (NM_024570.3 c.529G>A) in RNASEH2B has been reported in >50 homozygous and 7 compound heterozygous individuals with Aicardi-Goutieres sy ndrome related disorders (progressive spastic paraplegia), and segregated with d isease in at least 2 siblings (Rump 2016, Rice 2007, Crow 2006, Crow 2014, La Pi ana 2014, Crow 2015 and Ramatani 2010). Another >50 individuals were heterozygou s for this variant, though it is unclear if they were compound heterozygous for another variant in this gene or not. Although a second variant was not identifie d in a large number of individuals, the allele frequency in cases is statistical ly significantly increased compared to the general population (168/446 from lite rature vs 128/66494 ExAC, p value 0.0001 (Chi-square with Yates correction), sug gesting a causative role. This variant has also been reported in ClinVar (Variat ion ID#1262) as pathogenic by multiple laboratories. In vitro functional studies provide conflicting data ( Lim 2015 and Pizzi 2015). Homozygous mouse models de monstrate phenotypes similar to Aicardi-Goutieres syndrome (Mackenzie 2016). Thi s variant has been identified in 0.19% (128/66494) of European chromosomes by th e Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs75 184679). Although this variant has been seen in the general population, its freq uency is low enough to be consistent with a recessive carrier frequency. In summ ary, although additional studies are required to fully establish its clinical si gnificance, the p.Ala177Thr variant is likely pathogenic for Aicardi-Goutieres s yndrome in an autosomal recessive manner based upon segregation studies, animal models, functional evidence and its occurrence in patients with this disease.

Comment:

The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 16845400). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 4 similarly affected unrelated individuals (PMID: 16845400)(PM3_VS). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 26903602). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.614>=0.6). The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency:0.0015308). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

This variant is predicted to be damaging by in-silico missense prediction tools (SIFT and Polyphen2). The variant was previously reported in individuals with Aicardi-Goutieres syndrome in homozygous as well as compound heterozygous state and segregated with the disease [PMID: 16845400, 17846997, 18754903, 26182405, 26846091, 25604658]. Functional studies have shown that this variant affects RNASEH2B function [PMID: 19015152, 19034401, 26903602].

Comment:

This variant is interpreted as a Likely Pathogenic, for Aicardi-Goutieres syndrome 2, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PM3 => For recessive disorders, detected in trans with a pathogenic variant (PMID:16845400). PS3-Moderate => PS3 downgraded in strength to Moderate (PMID:25274781). PS4-Moderate => Recurrent mutation observed in multiple unrelated patients. (PMID:16845400,17846997,20131292,26846091,28762473).

Comment:

The c.529G>A;p.(Ala177Thr) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID:1262; PMID: 29691679; 29239743; 16845400; 17846997;28762473) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID:25274781; 19015152, 26903602) - PS3_moderate. The variant is present at low allele frequencies population databases (rs75184679 – gnomAD 0.01452%; ABraOM 0.002989 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Ala177Thr) was detected in trans with a pathogenic variant (PMID: 16845400; 17846997; 28762473) - PM3. The variant co-segregated with disease in multiple affected family members (PMID: 28762473) - PP1. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic.

Comment:

RNASEH2B NM_024570.3 exon 7 p.Ala177Thr (c.529G>A):This variant has been reported in the literature in numerous individuals with Aicardi-Goutieres syndrome (AGS) in the compound heterozygous and homozygous state and is reported to be the most common pathogenic variant associated with this condition (Selected publications: Crow 2006 PMID:16845400, Al-Mutairi 2018 PMID:29239743, Issa 2020 PMID:32404165, Videira 2020 PMID:32258229). This variant is present in 0.2% (40/15278) of Latino alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/13-50945445-G-A?dataset=gnomad_r3). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as Pathogenic or Likely Pathogenic (Variation ID:1262). Evolutionary conservation and computational predictive tools for this variant are unclear. Functional studies, including a knock-in mouse model predict that this variant will impact the protein and result in downstream instability (Lim 2015 PMID:26182405, Pizzi 2015 PMID:25274781, Mackenzie 2016 PMID:26903602). However, these studies may not accurately represent in vivo biological function and at least one study suggests that the ribonuclease H activities from this variant were comparable to WT (Perrino 2009 PMID:19034401). In summary, this variant is classified as pathogenic based on the data above.

Comment:

Variant summary: RNASEH2B c.529G>A (p.Ala177Thr) results in a non-conservative amino acid change located in the Ribonuclease H2 subunit B, wHTH domain (IPR019024) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0014 in 251300 control chromosomes. c.529G>A has been widely reported in the literature as homozygous and compound heterozygous genotypes in multiple individuals affected with Aicardi Goutieres Syndrome (example, Crow_2006, Beysen_2021). These data indicate that the variant is very likely to be associated with disease. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

This variant was identified in a 5 year old female with profound intellectual disability, arching, irritability, stereotypy, sleep problems, axial hypotonia, lower extremity hypertonia, optic nerve hypoplasia, feeding problems, plagiocephaly, slender fingers, and slender big toe. A brain MRI at age 3 months showed some thinning of falx cerebri. This variant has been reported previously in the literature and ClinVar as pathogenic. A second RNASEH2B variant was not identified, adequate sequence coverage was verified and deletion/duplication analysis was also normal. Additional genetic testing, including chromosomal microarray and mitochondrial DNA sequencing and deletion analysis, have not yielded a diagnosis.

Comment:

The RNASEH2B c.529G>A (p.Ala177Thr) missense variant results in the substitution of alanine at amino acid position 177 with threonine. Across a selection of the available literature, this variant has been reported in at least 22 individuals in a homozygous state and at least 12 individuals in a compound heterozygous state, including a sibling pair (PMID: 25604658; PMID: 29239743; PMID: 31130681; PMID: 30826161; PMID: 18754903). The highest frequency of this allele in the Genome Aggregation Database is 0.002618 in the Latino/Admixed American population (version 3.1.2). This frequency is consistent with the fact that it is the mostly commonly identified variant in individuals with Aicardi-Goutieres syndrome (PMID: 25243380; PMID: 31130681). Structural and functional studies, including in patient fibroblasts and mouse embryonic fibroblasts from an orthologous knock-in model, have demonstrated that the p.Ala177Thr substitution reduces RNase H2 subunit expression, disrupts the interaction interface of RNASEH2B with RNASEH2C, impairs complex stability, and reduces cellular RNase H2 activity (PMID: 26903602; PMID: 21177858; PMID: 21177854). Homozygous knock-in mice also recapitulate the interferon-stimulated gene signature observed in human patients with Aicardi-Goutieres syndrome. Based on the available evidence, the c.529G>A (p.Ala177Thr) variant is classified as pathogenic for Aicardi-Goutieres syndrome.

Comment:

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 177 of the RNASEH2B protein (p.Ala177Thr). This variant is present in population databases (rs75184679, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Aicardi-Gouti√®res syndrome, and unspecified neurological disorders (PMID: 16845400, 17846997, 18754903, 19694776, 20131292, 25243380, 25343331, 25604658, 26182405, 26846091). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1262). 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 have shown that this missense change affects RNASEH2B function (PMID: 19015152, 19034401, 26903602). For these reasons, this variant has been classified as Pathogenic.

Comment:

The c.529G>A (p.A177T) alteration is located in exon 7 (coding exon 7) of the RNASEH2B gene. This alteration results from a G to A substitution at nucleotide position 529, causing the alanine (A) at amino acid position 177 to be replaced by a threonine (T). Based on data from gnomAD, the A allele has an overall frequency of 0.14% (386/282704) total alleles studied. The highest observed frequency was 0.22% (290/129040) of European (non-Finnish) alleles. This variant has been identified in multiple homozygous individuals with Aicardi-Goutières Syndrome (Rice, 2007; Crow, 2015; Videira, 2020; Beysen, 2021). This amino acid position is not well conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic.

Comment:

The RNASEH2B c.529G>A (p.Ala177Thr) variant has been reported in the homozygous and compound heterozygous state in many individuals affected with AGS and related disorders (Beysen D et al., PMID: 33967934; Crow YJ et al., PMID: 16845400; Lambe J et al., PMID: 31920009; Pizzi S et al., PMID: 25274781; Rice G et al., PMID: 17846997; Videira G et al., PMID: 32258229). In at least three families, affected individuals who were homozygous for this variant showed marked intrafamilial and interfamilial phenotypic variability (Videira G et al., PMID: 32258229). This variant has been reported in the ClinVar database as a germline pathogenic or likely pathogenic variant in by several submitters. The highest population minor allele frequency in the population database genome aggregation database (v.2.1.1) is 0.2% in the European (non-Finnish) population which is compatible with carrier status for AGS and consistent with this variant being the most commonly identified causative variant (Rice G et al., PMID: 17846997). While computational predictors are uncertain as to the impact of this variant on the RNASEH2B protein, functional studies have shown a modest alteration of enzymatic activity and homozygous knock-in mice recapitulate the interferon-stimulated gene signature observed in human patients with AGS (Chon H et al., PMID: 19015152; Mackenzie KJ et al., PMID: 26903602; Perrino FW et al., PMID: 19034401; Pizzi S et al., PMID: 25274781). Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic.

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 of disease in this gene and is associated with Aicardi-Goutieres syndrome 2 (MIM#610181). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Severity varies among patients (OMIM, PMID: 32258229). (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to threonine. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2 & v3: 570 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated RNase H2 complex component wHTH domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as likely pathogenic and pathogenic in multiple individuals (ClinVar) and as homozygous in five patients from three families with differing presentations of Aicardi-Goutieres syndrome (PMID: 32258229). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Comment:

Lymphoblastoid cells derived from a patient who harbored the A177T variant showed a destabilizing effect on the RNase H2 protein; however, it is unclear if this perturbation is solely due to the effect of the A177T variant (PMID: 25274781); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis supports that this missense variant does not alter protein structure/function; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: no PMID, 33177673, 34490615, 33872687, 34758253, 31980526, 16845400, 19034401, 26903602, 21177854, 25604658, 27539236, 25343331, 26182405, 33967934, 33307271, 29030706, 29691679, 29239743, 30609409, 30223285, 30111349, 31367981, 31529068, 31920009, 31130284, 32258229, 32404165, 34573280, 25500883, 34426522, 31589614, 33258288, 32342562, 27943079, 34042169, 25274781, 25243380)

Comment:

The p.Ala177Thr variant in the RNASEH2B gene has been previously reported in >20 unrelated individuals with Aicardi-GoutiÃ¨res syndrome (Garau et al., 2019). All individuals were homozygous or compound heterozygous. This variant has also been identified in 290/129,040 European (non-Finnish) chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Well-established in vivo and in vitro functional studies of the p.Ala177Thr variant strongly suggest a deleterious effect to the protein that is sufficient to be disease-causing (Mackenzie et al., 2016; Pizzi et al., 2014). These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Ala177Thr variant as pathogenic for autosomal recessive Aicardi-GoutiÃ¨res syndrome based on the information above. [ACMG evidence codes used: PS3; PM3_Strong

Comment:

The RNASEH2B c.529G>A variant is predicted to result in the amino acid substitution p.Ala177Thr. This is the most common causative variant in the RNASEH2B gene. The c.529G>A variant has been observed in over twenty unrelated families to be causative for Aicardi-Goutiéres syndrome and in two families with uncomplicated spastic paraplegia (Crow et al. 2006. PubMed ID: 16845400; Crow et al. 2014. PubMed ID: 25243380; Rice et al. 2007. PubMed ID: 17846997). Functional studies have shown that this variant destabilizes the RNase H2 protein complex (Pizzi et al. 2015. PubMed ID: 25274781). In summary, we classify this variant 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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
A case report of two Moroccan patients with hereditary neurological disorders and molecular modeling study on the S72L de novo PMP22 variant.	Ait El Cadi C	Revue neurologique	2023	PMID: 37296061
Molecular characterization of an intronic RNASEH2B variant in a patient with Aicardi-Goutières syndrome.	Leung ML	European journal of medical genetics	2023	PMID: 36775013
[Aicardi-Goutieres syndrome: a family case due to alteration of the RNASEH2B gene].	Viguera-Elías D	Revista de neurologia	2021	PMID: 34042169
Genetic Testing Contributes to Diagnosis in Cerebral Palsy: Aicardi-Goutières Syndrome as an Example.	Beysen D	Frontiers in neurology	2021	PMID: 33967934
Late-Onset Aicardi-Goutières Syndrome: A Characterization of Presenting Clinical Features.	Piccoli C	Pediatric neurology	2021	PMID: 33307271
Diagnostic power and clinical impact of exome sequencing in a cohort of 500 patients with rare diseases.	Quaio CRDC	American journal of medical genetics. Part C, Seminars in medical genetics	2020	PMID: 33258288
Molecular diagnosis in recessive pediatric neurogenetic disease can help reduce disease recurrence in families.	Issa MY	BMC medical genomics	2020	PMID: 32404165
Diagnosis of Aicardi-Goutières Syndrome in Adults: A Case Series.	Videira G	Movement disorders clinical practice	2020	PMID: 32258229
Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging.	Hou YC	Proceedings of the National Academy of Sciences of the United States of America	2020	PMID: 31980526
Relapsing-remitting clinical course expands the phenotype of Aicardi-Goutières syndrome.	Lambe J	Annals of clinical and translational neurology	2020	PMID: 31920009
Characterization of six recombinant human RNase H2 bearing Aicardi-Goutiéres syndrome causing mutations.	Nishimura T	Journal of biochemistry	2019	PMID: 31529068
RNASEH2B Related Adult-Onset Interferonopathy.	Briggs TA	Journal of clinical immunology	2019	PMID: 31367981
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
Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population.	Monies D	American journal of human genetics	2019	PMID: 31130284
Spontaneous MRI improvement and absence of cerebral calcification in Aicardi-Goutières syndrome: Diagnostic and disease-monitoring implications.	Tonduti D	Molecular genetics and metabolism	2019	PMID: 30826161
Interpretation of Genomic Sequencing Results in Healthy and Ill Newborns: Results from the BabySeq Project.	Ceyhan-Birsoy O	American journal of human genetics	2019	PMID: 30609409
RNASEH2B Pathogenic Gene Variant in Uncomplicated Hereditary Spastic Paraplegia: Report of a New Patient.	Spagnoli C	Neuropediatrics	2018	PMID: 30223285
Encephalopathies with intracranial calcification in children: clinical and genetic characterization.	Tonduti D	Orphanet journal of rare diseases	2018	PMID: 30111349
The impact of next-generation sequencing on the diagnosis of pediatric-onset hereditary spastic paraplegias: new genotype-phenotype correlations for rare HSP-related genes.	Travaglini L	Neurogenetics	2018	PMID: 29691679
Phenotypic and Molecular Spectrum of Aicardi-Goutières Syndrome: A Study of 24 Patients.	Al Mutairi F	Pediatric neurology	2018	PMID: 29239743
Rare ADAR and RNASEH2B variants and a type I interferon signature in glioma and prostate carcinoma risk and tumorigenesis.	Beyer U	Acta neuropathologica	2017	PMID: 29030706
Late diagnosis and atypical brain imaging of Aicardi-Goutières syndrome: are we failing to diagnose Aicardi-Goutières syndrome-2?	Svingen L	Developmental medicine and child neurology	2017	PMID: 28762473
cGAS-STING do it again: pivotal role in RNase H2 genetic disease.	Gentili M	The EMBO journal	2016	PMID: 27009121
Ribonuclease H2 mutations induce a cGAS/STING-dependent innate immune response.	Mackenzie KJ	The EMBO journal	2016	PMID: 26903602
Whole-exome sequencing is a powerful approach for establishing the etiological diagnosis in patients with intellectual disability and microcephaly.	Rump P	BMC medical genomics	2016	PMID: 26846091
Genome-wide DNA hypomethylation and RNA:DNA hybrid accumulation in Aicardi-Goutières syndrome.	Lim YW	eLife	2015	PMID: 26182405
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
Defective removal of ribonucleotides from DNA promotes systemic autoimmunity.	Günther C	The Journal of clinical investigation	2015	PMID: 25500883
Reduction of hRNase H2 activity in Aicardi-Goutières syndrome cells leads to replication stress and genome instability.	Pizzi S	Human molecular genetics	2015	PMID: 25274781
FGFR3 mutation frequency in 324 cases from the International Skeletal Dysplasia Registry.	Xue Y	Molecular genetics & genomic medicine	2014	PMID: 25614871
Spastic paraparesis and marked improvement of leukoencephalopathy in Aicardi-Goutières syndrome.	La Piana R	Neuropediatrics	2014	PMID: 25343331
Mutations in ADAR1, IFIH1, and RNASEH2B presenting as spastic paraplegia.	Crow YJ	Neuropediatrics	2014	PMID: 25243380
Neuroimaging and neurological findings in patients with hypochondroplasia and FGFR3 N540K mutation.	Linnankivi T	American journal of medical genetics. Part A	2012	PMID: 23165795
Aicardi-Goutieres syndrome: from patients to genes and beyond.	Chahwan C	Clinical genetics	2012	PMID: 22149989
The structural and biochemical characterization of human RNase H2 complex reveals the molecular basis for substrate recognition and Aicardi-Goutières syndrome defects.	Figiel M	The Journal of biological chemistry	2011	PMID: 21177858
The structure of the human RNase H2 complex defines key interaction interfaces relevant to enzyme function and human disease.	Reijns MA	The Journal of biological chemistry	2011	PMID: 21177854
Expanding the phenotypic spectrum of lupus erythematosus in Aicardi-Goutières syndrome.	Ramantani G	Arthritis and rheumatism	2010	PMID: 20131292
Elevated pterins in cerebral spinal fluid--biochemical marker of Aicardi-Goutières syndrome.	Wassmer E	Developmental medicine and child neurology	2009	PMID: 19694776
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
Aicardi-Goutières syndrome: description of a late onset case.	D'Arrigo S	Developmental medicine and child neurology	2008	PMID: 18754903
Aicardi-Goutières syndrome presenting atypically as a sub-acute leukoencephalopathy.	Orcesi S	European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society	2008	PMID: 18069026
Clinical and molecular phenotype of Aicardi-Goutieres syndrome.	Rice G	American journal of human genetics	2007	PMID: 17846997
Mutations in genes encoding ribonuclease H2 subunits cause Aicardi-Goutières syndrome and mimic congenital viral brain infection.	Crow YJ	Nature genetics	2006	PMID: 16845400
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=RNASEH2B	-	-	-	-
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Text-mined citations for rs75184679 ...

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Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_024570.4(RNASEH2B):c.529G>A (p.Ala177Thr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs75184679 ...