Submissions for variant NM_004813.4(PEX16):c.616C>G (p.Leu206Val)

gnomAD frequency: 0.00004  dbSNP: rs375515674

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001105496	SCV001262464	uncertain significance	Peroxisome biogenesis disorder 8A (Zellweger)	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae	RCV001361646	SCV001557625	uncertain significance	Peroxisome biogenesis disorder	2022-10-04	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 206 of the PEX16 protein (p.Leu206Val). This variant is present in population databases (rs375515674, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with PEX16-related conditions. ClinVar contains an entry for this variant (Variation ID: 878685). 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 PEX16 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
PreventionGenetics, part of Exact Sciences	RCV003918684	SCV004732776	uncertain significance	PEX16-related condition	2024-02-08	criteria provided, single submitter	clinical testing	The PEX16 c.616C>G variant is predicted to result in the amino acid substitution p.Leu206Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0079% 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.