Submissions for variant NM_001111.5(ADAR):c.3233G>A (p.Arg1078His)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003781361	SCV004573217	uncertain significance	Symmetrical dyschromatosis of extremities; Aicardi-Goutieres syndrome 6	2023-07-07	criteria provided, single submitter	clinical testing	This variant disrupts the p.Arg1078 amino acid residue in ADAR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15489923). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. Advanced 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 at Invitae 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. This missense change has been observed in individual(s) with dyschromatosis symmetrica hereditaria (PMID: 29185800). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1078 of the ADAR protein (p.Arg1078His).
PreventionGenetics, part of Exact Sciences	RCV004539127	SCV004711724	uncertain significance	ADAR-related disorder	2024-01-16	no assertion criteria provided	clinical testing	The ADAR c.3233G>A variant is predicted to result in the amino acid substitution p.Arg1078His. This variant has been reported in the heterozygous state in an individual with dyschromatosis symmetrica hereditaria (Tang et al. 2018. PubMed ID: 29185800) and in a large cohort of individuals with developmental and epileptic encephalopathy (reported as c.3362G>A, p.Arg1121His in Table S4, Takata et al. 2019. PubMed ID: 31175295). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.