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

gnomAD frequency: 0.00141  dbSNP: rs75184679

Total submissions: 46

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000274058	SCV000329498	pathogenic	not provided	2023-07-18	criteria provided, single submitter	clinical testing	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 (Pizzi et al., 2015); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: no PMID, 33177673, 34490615, 33872687, 34758253, 31980526, 16845400, 19034401, 26903602, 21177854, 25604658, 25243380, 27539236, 25343331, 26182405, 33967934, 33307271, 29030706, 29691679, 29239743, 30609409, 30223285, 30111349, 31367981, 31529068, 31920009, 31130284, 32258229, 32404165, 34573280, 25500883, 34426522, 31589614, 33258288, 32342562, 25274781, 27943079, 34042169)
Eurofins Ntd Llc (ga)	RCV000274058	SCV000340736	pathogenic	not provided	2018-08-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000001324	SCV000384595	pathogenic	Aicardi-Goutieres syndrome 2	2023-01-09	criteria provided, single submitter	clinical testing	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000343151	SCV000540198	likely pathogenic	Aicardi Goutieres syndrome	2017-05-31	criteria provided, single submitter	clinical testing	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.
Athena Diagnostics Inc	RCV000274058	SCV000614883	pathogenic	not provided	2017-01-06	criteria provided, single submitter	clinical testing
Invitae	RCV000001324	SCV000652369	pathogenic	Aicardi-Goutieres syndrome 2	2024-01-31	criteria provided, single submitter	clinical testing	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-Goutières 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.
SIB Swiss Institute of Bioinformatics	RCV000001324	SCV000803481	likely pathogenic	Aicardi-Goutieres syndrome 2	2018-05-31	criteria provided, single submitter	curation	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).
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System	RCV000001324	SCV000804384	pathogenic	Aicardi-Goutieres syndrome 2	2017-03-17	criteria provided, single submitter	provider interpretation	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.
Fulgent Genetics, Fulgent Genetics	RCV000001324	SCV000894013	pathogenic	Aicardi-Goutieres syndrome 2	2018-10-31	criteria provided, single submitter	clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000001324	SCV000965776	pathogenic	Aicardi-Goutieres syndrome 2	2015-01-01	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000001324	SCV001132538	pathogenic	Aicardi-Goutieres syndrome 2	2018-11-15	criteria provided, single submitter	research	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.
Mendelics	RCV000001324	SCV001139343	pathogenic	Aicardi-Goutieres syndrome 2	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000274058	SCV001247787	pathogenic	not provided	2024-02-01	criteria provided, single submitter	clinical testing	RNASEH2B: PM3:Very Strong, PM2, PS3:Supporting
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000001324	SCV001369896	likely pathogenic	Aicardi-Goutieres syndrome 2	2018-12-10	criteria provided, single submitter	clinical testing	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PP2,PP3,PS3.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000001324	SCV001429537	pathogenic	Aicardi-Goutieres syndrome 2	2024-02-20	criteria provided, single submitter	clinical testing	Criteria applied: PM3_VSTR,PS3_MOD
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München	RCV000001324	SCV001430042	pathogenic	Aicardi-Goutieres syndrome 2	2020-07-21	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000274058	SCV001447813	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Laboratoire de Génétique Moléculaire, CHU Bordeaux	RCV000274058	SCV001468967	likely pathogenic	not provided		criteria provided, single submitter	clinical testing
New York Genome Center	RCV000001324	SCV001480396	pathogenic	Aicardi-Goutieres syndrome 2	2020-04-24	criteria provided, single submitter	clinical testing
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001813931	SCV001755491	pathogenic	Abnormality of the nervous system	2021-07-10	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000274058	SCV002010692	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000001324	SCV002019058	likely pathogenic	Aicardi-Goutieres syndrome 2	2022-04-18	criteria provided, single submitter	clinical testing
Centogene AG - the Rare Disease Company	RCV000001324	SCV002059737	pathogenic	Aicardi-Goutieres syndrome 2	2020-07-27	criteria provided, single submitter	clinical testing
DASA	RCV000001324	SCV002061178	pathogenic	Aicardi-Goutieres syndrome 2	2022-01-05	criteria provided, single submitter	clinical testing	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.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000001324	SCV002061858	pathogenic	Aicardi-Goutieres syndrome 2	2021-04-16	criteria provided, single submitter	clinical testing	PM3_Strong, PS3
3billion	RCV000001324	SCV002318806	pathogenic	Aicardi-Goutieres syndrome 2	2022-03-22	criteria provided, single submitter	clinical testing	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.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000001324	SCV002495930	pathogenic	Aicardi-Goutieres syndrome 2	2021-04-16	criteria provided, single submitter	clinical testing	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.
AiLife Diagnostics, AiLife Diagnostics	RCV000274058	SCV002501985	likely pathogenic	not provided	2021-07-01	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000001324	SCV002512642	pathogenic	Aicardi-Goutieres syndrome 2	2021-10-14	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3 supporting, PM3 very strong, PP1 strong, PP1 supporting
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000343151	SCV002547569	pathogenic	Aicardi Goutieres syndrome	2022-05-31	criteria provided, single submitter	clinical testing	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.
MGZ Medical Genetics Center	RCV000001324	SCV002581269	likely pathogenic	Aicardi-Goutieres syndrome 2	2021-10-29	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000001324	SCV002767048	pathogenic	Aicardi-Goutieres syndrome 2	2022-06-24	criteria provided, single submitter	clinical testing	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) 0251 - This variant is heterozygous. (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 heterozygotes, 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 regarded likely pathogenic and pathogenic in multiple individuals (ClinVar, 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
Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine	RCV003125824	SCV003804031	pathogenic	Autism spectrum disorder	2022-08-05	criteria provided, single submitter	clinical testing
Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL)	RCV000001324	SCV003920813	pathogenic	Aicardi-Goutieres syndrome 2	2023-04-27	criteria provided, single submitter	research
PreventionGenetics, part of Exact Sciences	RCV003415614	SCV004106595	pathogenic	RNASEH2B-related condition	2023-07-31	criteria provided, single submitter	clinical testing	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.
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000001324	SCV004171884	pathogenic	Aicardi-Goutieres syndrome 2		criteria provided, single submitter	clinical testing
OMIM	RCV000001324	SCV000021474	pathogenic	Aicardi-Goutieres syndrome 2	2014-12-01	no assertion criteria provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000001324	SCV000733351	pathogenic	Aicardi-Goutieres syndrome 2		no assertion criteria provided	clinical testing
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	RCV000274058	SCV000778237	pathogenic	not provided	2017-01-26	no assertion criteria provided	clinical testing
Clinical Genomics Program, Stanford Medicine	RCV000001324	SCV001427209	pathogenic	Aicardi-Goutieres syndrome 2	2019-12-05	no assertion criteria provided	clinical testing	The p.Ala177Thr variant in the RNASEH2B gene has been previously reported in >20 unrelated individuals with Aicardi-Goutières 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-Goutières syndrome based on the information above. [ACMG evidence codes used: PS3; PM3_Strong
Centre of Medical Genetics, University of Antwerp	RCV001293274	SCV001481865	pathogenic	Cerebral palsy		no assertion criteria provided	clinical testing	missense mutation, previously described as pathogenic in the literature and in ClinVar
Génétique des Maladies du Développement, Hospices Civils de Lyon	RCV000001324	SCV001623555	pathogenic	Aicardi-Goutieres syndrome 2		no assertion criteria provided	clinical testing
Genomics England Pilot Project, Genomics England	RCV000001324	SCV001760322	pathogenic	Aicardi-Goutieres syndrome 2		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000274058	SCV001809098	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000274058	SCV001932543	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000274058	SCV001967818	pathogenic	not provided		no assertion criteria provided	clinical testing