ClinVar Miner

Submissions for variant NM_001111.5(ADAR):c.577C>G (p.Pro193Ala) (rs145588689)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000624331 SCV000742076 pathogenic Inborn genetic diseases 2017-05-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
ClinVar Staff, National Center for Biotechnology Information (NCBI) RCV000114336 SCV000244001 likely pathogenic Aicardi-Goutieres syndrome 6 2013-06-27 no assertion criteria provided literature only
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000255775 SCV000332712 pathogenic not provided 2015-12-18 criteria provided, single submitter clinical testing
GeneDx RCV000255775 SCV000321382 uncertain significance not provided 2018-11-02 criteria provided, single submitter clinical testing The P193A pathogenic variant in the ADAR gene has been reported previously in combination with another ADAR variant in several individuals with Aicardi-Goutieres syndrome or bilateral striatal necrosis and dystonia (Rice et al., 2012; Livingston et al., 2014). The P193A variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This variant is located within the Z-DNA/Z-RNA binding domain of the protein (Rice et al., 2012). Conflicting evidence has been reported regarding the effect of this variant on protein function and structure (Mannion et al., 2014; Kono et al., 2018). The P193A variant is observed in 418/126,682 (0.33%) alleles from individuals of non-Finnish European background, including one homozygous individual, in large population cohorts (Lek et al., 2016). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
GeneReviews RCV000114336 SCV000147906 pathogenic Aicardi-Goutieres syndrome 6 2014-03-13 no assertion criteria provided literature only
Illumina Clinical Services Laboratory,Illumina RCV000288094 SCV000348566 likely benign Symmetrical dyschromatosis of extremities 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000352411 SCV000348567 likely benign Aicardi Goutieres syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000778185 SCV000914349 pathogenic ADAR-Related Disorders 2018-05-11 criteria provided, single submitter clinical testing The ADAR c.577C>G (p.Pro193Ala) missense variant has been reported in at least three studies in which it is found in a compound heterozygous state in at least 15 probands with ADAR-related disorders, including two sets of siblings and eight affected individuals from five families (Rice et al. 2012; Livingston et al. 2014; Schmelzer et al. 2018). The p.Pro193Ala variant has not been found in any affected individuals with dyschromatosis symmetrica hereditaria. Affected probands exhibited acute or subacute onset of striatal necrosis, early-onset encephalopathy, intracranial calcifications, developmental delay, severe and progressive dystonia, and often exhibited bilateral striatal necrosis (Rice et al. 2012; Livingston et al. 2014). Control data are unavailable for this variant, which is reported at a frequency of 0.003976 in the European population of the 1000 Genomes Project and observed in one homozygote in the Genome Aggregation Database. The p.Pro193Ala variant is reasonably common in the general population but still present at a frequency consistent with autosomal recessive disease. It is also noted that variants in the ADAR gene may have an atypical or milder presentation (Crow et al. 2016). Expression analysis of p.Pro193Ala in HEK293 cells showed a significant reduction in RNA-editing enzyme activity (Mannion et al. 2014). The loss of ADAR in hematopoietic stem cells in mice was associated with upregulation of type-I and type-II interferon-inducible transcripts and rapid apoptosis (Hartner et al. 2009). Based on the evidence, the p.Pro193Ala variant is classified as pathogenic for ADAR-Related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Institute of Human Genetics,Klinikum rechts der Isar RCV000114336 SCV000680137 pathogenic Aicardi-Goutieres syndrome 6 2017-09-08 criteria provided, single submitter clinical testing
Invitae RCV000548694 SCV000652396 uncertain significance Symmetrical dyschromatosis of extremities; Aicardi-Goutieres syndrome 6 2019-01-01 criteria provided, single submitter clinical testing This sequence change replaces proline with alanine at codon 193 of the ADAR protein (p.Pro193Ala). The proline residue is moderately conserved and there is a small physicochemical difference between proline and alanine. This variant is present in population databases (rs145588689, ExAC 0.3%). This variant has been reported in multiple individuals and families affected with ADAR-related diseases (PMID: 26629815, 23001123). ClinVar contains an entry for this variant (Variation ID: 126395). This variant has been shown to significantly affect RNA editing activity and causes slight reduction in DNA binding function of the encoded protein (PMID: 25456137, 9889202). In summary, this variant is a rare missense change that has been reported in affected individuals and shown to impact protein function. However, it is also observed in the general population at an appreciable frequency. Additional data are needed to ascertain the clinical impact of this variant. For these reasons, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000352411 SCV000711724 likely pathogenic Aicardi Goutieres syndrome 2017-04-28 criteria provided, single submitter clinical testing The p.Pro193Ala (NM_001111.4 c.577C>G) variant in ADAR has been reported in at l east 8 affected individuals (two of whom were identical twins) from 5 families w ith Aicardi-Goutieres syndrome (Rice 2012) and 6 individuals from 5 families wit h bilateral striatal necrosis (Livingston 2014). All affected individuals were c ompound heterozygotes with a second ADAR variant. This variant has also been rep orted in ClinVar (Variation ID# 126395). The p.Pro193Ala variant has also been i dentified in 0.3% (199/66,740) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs145588689). Although t his variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency (of note, the prevalence of the disease is unknown). Computational prediction tools and conservation analys is suggest that the p.Pro193Ala variant may impact the protein, though this info rmation is not predictive enough to determine pathogenicity. In summary, althoug h additional studies are required to fully establish its clinical significance, the p.Pro193Ala variant is likely pathogenic based on its occurrence in individu als with this disease.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000548694 SCV000782783 likely pathogenic Symmetrical dyschromatosis of extremities; Aicardi-Goutieres syndrome 6 2018-02-15 criteria provided, single submitter clinical testing
OMIM RCV000114336 SCV000056412 pathogenic Aicardi-Goutieres syndrome 6 2014-02-01 no assertion criteria provided literature only

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