Submissions for variant NM_001278293.3(ARL6):c.362G>A (p.Arg121His)

gnomAD frequency: 0.00001  dbSNP: rs765715798

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Department Of Translational Genomics (developmental Genetics Section), King Faisal Specialist Hospital & Research Centre	RCV000171364	SCV000221561	likely pathogenic	not provided		criteria provided, single submitter	research
Invitae	RCV001852067	SCV002169020	likely pathogenic	Bardet-Biedl syndrome 3; Retinitis pigmentosa 55	2023-11-13	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 121 of the ARL6 protein (p.Arg121His). This variant is present in population databases (rs765715798, gnomAD 0.007%). This missense change has been observed in individuals with clinical features of ARL6-related conditions (PMID: 26355662, 28130426, 35457050; Invitae). ClinVar contains an entry for this variant (Variation ID: 191178). 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. This variant disrupts the p.Arg121 amino acid residue in ARL6. Other variant(s) that disrupt this residue have been observed in individuals with ARL6-related conditions (PMID: 33090715), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002469042	SCV002766550	likely pathogenic	Bardet-Biedl syndrome	2022-11-21	criteria provided, single submitter	clinical testing	Variant summary: ARL6 c.362G>A (p.Arg121His) results in a non-conservative amino acid change located in the small GTP-binding protein domain (IPR005225) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 250632 control chromosomes (gnomAD). The variant, c.362G>A, has been reported in the literature in at least three homozygous individuals affected with retinal dystrophy (Patel_2016, Abouelhoda_2016, Biswas_2017, Ramkumar_2017, Gonzalez-Iglesias_2022). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A different missense change affecting the same amino acid (c.361C>T (p.R121C)) is reported in individual(s) affected with retinal dystrophy (HGMD), suggesting a functional role for this residue. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic (n=1) and uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002485089	SCV002787227	uncertain significance	Bardet-Biedl syndrome 1; Bardet-Biedl syndrome 3; Retinitis pigmentosa; Retinitis pigmentosa 55	2021-07-06	criteria provided, single submitter	clinical testing
GeneDx	RCV000171364	SCV003845452	uncertain significance	not provided	2022-09-20	criteria provided, single submitter	clinical testing	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: 26355662, 27124789, 33090715, 28130426, 28005406)
Faculty of Health Sciences, Beirut Arab University	RCV001257839	SCV001434702	pathogenic	Autosomal recessive retinitis pigmentosa	2015-09-10	no assertion criteria provided	literature only