Submissions for variant NM_001111.5(ADAR):c.3095G>A (p.Arg1032His)

gnomAD frequency: 0.00001  dbSNP: rs773129591

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000441679	SCV000529369	uncertain significance	not provided	2016-06-27	criteria provided, single submitter	clinical testing	The R1032H variant in the ADAR gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R1032H variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R1032H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. A missense variant in a nearby residue, M1034V, has been reported in the Human Gene Mutation Database in association with Aicardi-Goutieres syndrome and missense variants in nearby residues, M1034V, C1036Y, and C1036S have been reported in association with Dyschromatosis symmetrica hereditaria (Stenson et al., 2014), supporting the functional importance of this region of the protein.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001068705	SCV001233832	uncertain significance	Symmetrical dyschromatosis of extremities; Aicardi-Goutieres syndrome 6	2024-10-16	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1032 of the ADAR protein (p.Arg1032His). This variant is present in population databases (rs773129591, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with ADAR-related conditions. ClinVar contains an entry for this variant (Variation ID: 387356). Invitae Evidence 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 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 ADAR protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Genome-Nilou Lab	RCV003338589	SCV004050327	uncertain significance	Aicardi-Goutieres syndrome 6	2023-04-11	criteria provided, single submitter	clinical testing