Submissions for variant NM_001174150.2(ARL13B):c.626G>A (p.Arg209His)

dbSNP: rs199790565

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000425094	SCV000526949	uncertain significance	not provided	2016-05-03	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the ARL13B gene. The R209H variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R209H variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, but the 1000 Genomes Project reports it was observed in 2/1322 (0.2%) alleles from individuals of African background. This substitution occurs at a position that is conserved in mammals; however, Histidine is observed at this position in evolution. Additionally, the R209H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae	RCV001234582	SCV001407236	uncertain significance	Joubert syndrome 8	2022-10-05	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 209 of the ARL13B protein (p.Arg209His). This variant is present in population databases (rs199790565, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with ARL13B-related conditions. ClinVar contains an entry for this variant (Variation ID: 385624). 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) performed at Invitae indicates that this missense variant is not expected to disrupt ARL13B 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.