Submissions for variant NM_001278293.3(ARL6):c.529C>T (p.Leu177Phe)

gnomAD frequency: 0.00003  dbSNP: rs750627875

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001755657	SCV002005253	uncertain significance	not provided	2019-04-02	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously reported as pathogenic or benign to our knowledge; Observed in 7/33,560 (0.021%) alleles from individuals of Latino background, in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31054281)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001868764	SCV002176148	uncertain significance	Bardet-Biedl syndrome 3; Retinitis pigmentosa 55	2022-10-05	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 177 of the ARL6 protein (p.Leu177Phe). This variant is present in population databases (rs750627875, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of retinitis pigmentosa (PMID: 31054281). ClinVar contains an entry for this variant (Variation ID: 1319009). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Fulgent Genetics, Fulgent Genetics	RCV002503253	SCV002814951	uncertain significance	Bardet-Biedl syndrome 1; Bardet-Biedl syndrome 3; Retinitis pigmentosa; Retinitis pigmentosa 55	2022-04-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004782788	SCV005395085	uncertain significance	not specified	2024-09-10	criteria provided, single submitter	clinical testing	Variant summary: ARL6 c.529C>T (p.Leu177Phe) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251268 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.529C>T has been reported in the literature in individuals affected with Retinitis Pigmentosa (Gao_2019) without evidence for causality. These report(s) do not provide unequivocal conclusions about association of the variant with Bardet-Biedl Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 31054281). ClinVar contains an entry for this variant (Variation ID: 1319009). Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003407802	SCV004115110	uncertain significance	ARL6-related disorder	2024-01-03	no assertion criteria provided	clinical testing	The ARL6 c.529C>T variant is predicted to result in the amino acid substitution p.Leu177Phe. This variant has been observed in a patient with retinitis pigmentosa (Gao et al. 2019. PubMed ID: 31054281). However, no further evidence of pathogenicity was provided. Of note, we previously observed this variant at PreventionGenetics in a Bardet Biedl syndrome patient together with a known ARL6 pathogenic variant. This variant is reported in 0.023% of alleles in individuals of Latino descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.