Submissions for variant NM_000287.4(PEX6):c.1931G>A (p.Arg644Gln)

gnomAD frequency: 0.00001  dbSNP: rs746117128

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001163660	SCV001325721	uncertain significance	Peroxisome biogenesis disorder 4A (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	RCV001240731	SCV001413700	uncertain significance	Peroxisome biogenesis disorder	2022-09-01	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 644 of the PEX6 protein (p.Arg644Gln). This variant is present in population databases (rs746117128, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of Zellweger syndrome spectrum (PMID: 34055681). ClinVar contains an entry for this variant (Variation ID: 911291). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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	RCV002483916	SCV002787721	uncertain significance	Peroxisome biogenesis disorder 4A (Zellweger); Peroxisome biogenesis disorder 4B; Heimler syndrome 2	2021-09-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002558573	SCV003757200	uncertain significance	Inborn genetic diseases	2021-07-26	criteria provided, single submitter	clinical testing	The c.1931G>A (p.R644Q) alteration is located in exon 9 (coding exon 9) of the PEX6 gene. This alteration results from a G to A substitution at nucleotide position 1931, causing the arginine (R) at amino acid position 644 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357953	SCV001553566	uncertain significance	not provided		no assertion criteria provided	clinical testing	The PEX6 p.Arg644Gln variant was not identified in the literature nor was it identified in ClinVar, Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs746117128) and was found in control databases in 13 of 282672 chromosomes at a frequency of 0.000046 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 7 of 35440 chromosomes (freq: 0.000198), Other in 1 of 7220 chromosomes (freq: 0.000139), European (Finnish) in 1 of 25030 chromosomes (freq: 0.00004) and European (non-Finnish) in 4 of 129098 chromosomes (freq: 0.000031), while the variant was not observed in the African, Ashkenazi Jewish, East Asian and South Asian populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Arg644 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Natera, Inc.	RCV001828577	SCV002077291	uncertain significance	Zellweger spectrum disorders	2020-04-28	no assertion criteria provided	clinical testing