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

dbSNP: rs398122822

Total submissions: 16

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 Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	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.
Invitae	RCV000762850	SCV002237768	pathogenic	Symmetrical dyschromatosis of extremities; Aicardi-Goutieres syndrome 6	2023-09-13	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this missense change affects ADAR function (PMID: 26802932, 29775506). 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. ClinVar contains an entry for this variant (Variation ID: 39458). 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. This variant is not present in population databases (gnomAD no frequency). 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.
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
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