ClinVar Miner

Submissions for variant NM_024570.4(RNASEH2B):c.529G>A (p.Ala177Thr) (rs75184679)

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Total submissions: 20
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000274058 SCV000329498 pathogenic not provided 2018-11-30 criteria provided, single submitter clinical testing The A177T is the most commonly reported pathogenic variant in the RNASEH2B gene, and has been reported previously in association with classic Aicardi-Goutieres syndrome and the progressive spastic paraplegia phenotype when present in the homozygous state, or when in trans with another pathogenic variant (Crow et al., 2006; Crow et al., 2014; Crow et al., 2015). The A177T variant is observed in 281/126540 alleles (0.22%) from individuals of non-Finnish European background in the large population cohorts and no individuals were reported to be homozygous (Lek et al., 2016). The A177T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Although functional studies did not detect loss of ribonuclease H activity, in vitro analyses did indicate that the A177T variant has a destabilizing effect on the RNase H2 enzyme and/or the cellular action of the catalytic subunit, and leads to accumulation of rNMPs in chromosomal DNA (Perrino et al., 2009; Pizzi et al., 2015). We interpret A177T as a pathogenic variant.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000274058 SCV000340736 pathogenic not provided 2018-08-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000343151 SCV000384595 pathogenic Aicardi Goutieres syndrome 2016-06-14 criteria provided, single submitter clinical testing The c.529G>A (p.Ala177Thr) variant has been reported in at least four studies in which it is found in an unspecified number of affected individuals in a homozygous state in 48 Aicardi-Goutieres syndrome families and in a heterozygous state in 49 Aicardi-Goutieres syndrome families, in a homozygous state in ten patients (including two siblings), and in a heterozygous state in seven patients (Crow et al. 2006; Rice et al. 2007; Crow et al. 2014; Crow et al. 2015). Three of the heterozygous individuals in Crow et al. (2015) also carried a homozygous variant in a second gene. In the study by Rice et al. (2007) (which included the patients reported by Crow et al. 2006), the p.Ala177Thr variant accounted for 60 out of the 97 RNASEH2B variants detected, and was the most frequently identified pathogenic variant in all of the cases reviewed. The p.Ala177Thr variant was found in a heterozygous state in one of 582 control alleles and is reported at a frequency of 0.00291 in the European American population of the Exome Sequencing Project. Based on the collective evidence, the p.Ala177Thr variant is classified as pathogenic for Aicardi-Goutieres syndrome.
Laboratory for Molecular Medicine, Partners HealthCare 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 2019-12-28 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 177 of the RNASEH2B protein (p.Ala177Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs75184679, ExAC 0.2%). This variant has been reported in the homozygous state and in combination with other deleterious RNASEH2B variants in multiple individuals affected with Aicardi-Gouti res syndrome (PMID: 16845400, 25243380, 25343331, 26182405, 26846091, 17846997, 20131292, 18754903, 19694776). It has also been reported in several individuals with unspecified neurological disorders (PMID: 25604658). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 1262). Experimental studies have reported that this missense change has a mild effect on protein function in vitro and leads to a subclinical phenotype in mice that mimics some aspects of Aicardi-Gouti res syndrome (PMID: 19015152, 26903602). However, in another study it has been reported that this variant has no effect on RNASEH2B enzymatic activity in a bacterial cells (PMID: PMID: 19034401). 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 Institute Rare Disease Group,Broad Institute 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 Praxis fuer Humangenetik Tuebingen RCV000274058 SCV001247787 pathogenic not provided 2019-12-01 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001198901 SCV001369896 likely pathogenic Esotropia; Global developmental delay; Seizures; Poor eye contact; Congenital sensorineural hearing impairment 2018-12-10 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP4. This variant was detected in hemizygous state.
Institute of Human Genetics, University of Leipzig Medical Center RCV000001324 SCV001429537 pathogenic Aicardi Goutieres syndrome 2 2017-05-19 criteria provided, single submitter clinical testing
Institute of Human Genetics,Klinikum rechts der Isar RCV000001324 SCV001430042 pathogenic Aicardi Goutieres syndrome 2 2020-07-21 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

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