Submissions for variant NM_001111.5(ADAR):c.3019G>A (p.Gly1007Arg)

dbSNP: rs398122822

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
UCLA Clinical Genomics Center, UCLA	RCV000032653	SCV000255319	likely pathogenic	Symmetrical dyschromatosis of extremities	2013-05-14	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000032654	SCV000328705	pathogenic	Aicardi-Goutieres syndrome 6	2022-07-28	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000762850	SCV000893210	pathogenic	Symmetrical dyschromatosis of extremities; Aicardi-Goutieres syndrome 6	2018-10-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001091722	SCV001247915	pathogenic	not provided	2024-02-01	criteria provided, single submitter	clinical testing	ADAR: PS2, PM2, PS4:Moderate, PP3, PS3:Supporting
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000032654	SCV001368860	pathogenic	Aicardi-Goutieres syndrome 6	2019-03-17	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM2,PM5,PP3.
Johns Hopkins Genomics, Johns Hopkins University	RCV000032654	SCV001430630	pathogenic	Aicardi-Goutieres syndrome 6	2020-05-30	criteria provided, single submitter	clinical testing	This ADAR variant is absent from a large population dataset and has an entry in ClinVar. It has been reported in at least eleven individuals from nine families with autosomal dominant Aicardi-Goutieres syndrome. In four families, the c.3019G>A variant occurred de novo. Independent functional studies have shown that the p.Gly1007Arg substitution inhibits the RNA editing activity of ADAR1, presumably through steric hindrance at the base-flipping step of the deaminase reaction. We consider this variant to be pathogenic.
GeneDx	RCV001091722	SCV001805453	pathogenic	not provided	2022-04-05	criteria provided, single submitter	clinical testing	Reported in published literature in multiple affected individuals from a few unrelated families with dyschromatosis symmetrica hereditaria and neurodegeneration with dystonia and intracranial calcification. Also present in multiple unaffected relatives in these families, suggesting G1007R may exhibit incomplete penetrance (Suzuki et al., 2005; Kondo et al., 2008); Published functional studies suggest that G1007R may confer a dominant-negative effect by binding more tightly to RNA and acting as competitive inhibitor to the wild-type protein (Rice et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29775506, 24262145, 25243380, 19017046, 16817193, 27959697, 15955093, 23001123, 29691679, 31737037, 34426522, 32801363, 33307271, 27535533)
Neuberg Centre For Genomic Medicine, NCGM	RCV000032654	SCV002073235	pathogenic	Aicardi-Goutieres syndrome 6		criteria provided, single submitter	clinical testing	The missense variant p.G1007R in ADAR (NM_001111.5) has been previously reported in multiple individuals with dominant Aicardi Goutieres syndrome (Kondo T et al,2008). Functional analysis revealed a damagig effect (Fisher AJ et al,2017). The variant has been submitted to ClinVar as Pathogenic. The p.G1007R variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.G1007R missense variant is predicted to be damaging by both SIFT and PolyPhen2. The nucleotide c.3019 in ADAR is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000762850	SCV002237768	pathogenic	Symmetrical dyschromatosis of extremities; Aicardi-Goutieres syndrome 6	2024-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1007 of the ADAR protein (p.Gly1007Arg). This variant also falls at the last nucleotide of exon 11, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of autosomal dominant dyschromatosis symmetrica hereditaria and/or autosomal dominant Aicardi Goutieres syndrome (PMID: 15955093, 16817193, 19017046, 23001123, 24262145, 25243380, 28561207, 29691679, 32801363, 33307271). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 39458). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects ADAR function (PMID: 26802932, 29775506). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). For these reasons, this variant has been classified as Pathogenic.
Wangler Lab, Baylor College of Medicine	RCV000032654	SCV002587798	pathogenic	Aicardi-Goutieres syndrome 6		criteria provided, single submitter	clinical testing	This ADAR variant at c.3019G>A (p.G1007R) was seen on exome through the Texome project (R01HG011795). This variant has been described as a de novo variant in the heterozygous state in individuals with autosomal dominant Aicardi-Goutières syndrome (PMID: 23001123, 33307271) and in individuals with dyschromatosis symmetrica hereditaria with additional features including dystonia, mental deterioration and brain MRI abnormalities (PMID: 16817193, 19017046). In addition, this heterozygous variant has been described in two individuals with tremors, spasticity/dystonia, abnormal MRI findings and progressive motor deterioration (PMID: 24262145, 29691679) and two internal cases with a similar phenotype. This variant is absent from gnomAD (PM2). Functional studies suggest this variant showed a significant effect on editing function of the protein, with levels of editing equivalent to those seen with inactive protein (PMID: 23001123) (PS3). This heterozygous variant shows RNA editing deficiency similar to Aicardi-Goutières associated variants and more severely affected when compared to dyschromatosis symmetrica hereditaria associated variants (PMID: 26802932).This variant lies at the last nucleotide of exon 11 (of 15) for the reported transcript. This variant is predicted to be deleterious(CADD: 34.000, SpliceAI: 0.190) (PP3). The evolutionary conservation of this residue is high. Variant is located in the adenosinede aminase/editase domain (PMID: 23001123). We classify this variant as pathogenic.
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000032654	SCV002764954	pathogenic	Aicardi-Goutieres syndrome 6	2020-09-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000032654	SCV004050328	likely pathogenic	Aicardi-Goutieres syndrome 6	2023-04-11	criteria provided, single submitter	clinical testing
North West Genomic Laboratory Hub, Manchester University NHS Foundation Trust	RCV000762850	SCV004814241	likely pathogenic	Symmetrical dyschromatosis of extremities; Aicardi-Goutieres syndrome 6	2022-06-28	criteria provided, single submitter	clinical testing	Criteria Codes: PS3 PS4_Mod PM2 PP3
Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	RCV000032654	SCV005050191	pathogenic	Aicardi-Goutieres syndrome 6	2024-03-01	criteria provided, single submitter	clinical testing	The NM_001111.5: c.3019G>A variant is located in exon 11 of the ADAR gene. This variant involves a change at the protein level from Glycine to Arginine at position 1007 (p.(Gly1007Arg)). This position is highly conserved and corresponds to a well-established domain of the protein. This variant has a null frequency in population databases and, in turn, has numerous reports in ClinVar, where it is classified as likely pathogenic/pathogenic (ClinVarID: 39458). In addition, more than 4 cases have been reported in which the variant was found 'de novo' (PMID: 23001123, 33307271). On the other hand, bioinformatic tools predict that the variant would be deleterious, which agrees with what has been demonstrated through functional studies (PMID: 25243380, 26372505). It is important to highlight that, although patients with the AGS phenotype associated with an autosomal recessive inheritance pattern have been described, this particular variant behaves as dominant-negative, so affected patients are heterozygous for said variant. (PS3supporting, PM1supporting, PM2moderate, PM6strong, PP3moderate)
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000032654	SCV005061416	pathogenic	Aicardi-Goutieres syndrome 6	2024-06-17	criteria provided, single submitter	clinical testing	heterozygous
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000032654	SCV005400344	pathogenic	Aicardi-Goutieres syndrome 6	2021-05-06	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: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with AGS 6 (MIM#615010) and DSH (MIM#127400). The dominant negative mechanism has only been reported for a single variant (p.Gly1007Arg), whereas all other variants have been reported with a loss of function mechanism (PMID: 23001123, PMID: 28561207, OMIM). (I) 0108 - This gene is associated with both recessive and dominant disease. AGS is normally a recessive condition, caused by variants found within isoform p150. The p.(Gly1007Arg) variant is the only dominantly-acting variant to cause AGS. DHS is a dominant condition caused by variants found within isoform p110 (PMID: 25456137, PMID: 23001123). (I) 0112 - The condition associated with this gene has incomplete penetrance. This variant (p.Gly1007Arg) has been reported in probands with unaffected parents (PMID: 28561207). (I) 0115 - Variants in this gene are known to have variable expressivity (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located at the surface of the annotated catalytic domain (PMID: 23001123). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant have been reported many times as pathogenic (ClinVar), and been reported in multiple heterozygous patients with Aicardi-Goutieres syndrome (AGS), who either inherited the variant from unaffected parents, or the variant arose de novo. It has also been reported in several patients with dyschromatosis symmetrica hereditarian (DHS) (ClinVar, OMIM, PMID: 23001123, PMID: 28561207, PMID: 16817193). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Transfected HEK293 cells have been proven to have a significant reduction in editing activity (PMID: 23001123). (SP) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed) (LABID). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000032653	SCV000056416	pathogenic	Symmetrical dyschromatosis of extremities	2014-12-01	no assertion criteria provided	literature only
OMIM	RCV000032654	SCV000056417	pathogenic	Aicardi-Goutieres syndrome 6	2014-12-01	no assertion criteria provided	literature only
GeneReviews	RCV000032654	SCV000147905	not provided	Aicardi-Goutieres syndrome 6		no assertion provided	literature only
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000032654	SCV000244028	likely pathogenic	Aicardi-Goutieres syndrome 6	2013-06-27	no assertion criteria provided	literature only