Submissions for variant NM_000287.4(PEX6):c.1409G>C (p.Gly470Ala)

dbSNP: rs1561823098

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000694665	SCV000823122	pathogenic	Peroxisome biogenesis disorder	2023-06-29	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 470 of the PEX6 protein (p.Gly470Ala). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PEX6 protein function. ClinVar contains an entry for this variant (Variation ID: 573090). This missense change has been observed in individual(s) with Zellweger spectrum disorder (Invitae).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000694665	SCV000919978	pathogenic	Peroxisome biogenesis disorder	2023-08-16	criteria provided, single submitter	clinical testing	Variant summary: PEX6 c.1409G>C (p.Gly470Ala) results in a non-conservative amino acid change located in the AAA+ ATPase domain (IPR003593) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251216 control chromosomes (gnomAD). c.1409G>C has been reported in the literature in multiple individuals affected with Zellweger Syndrome (e.g., Schieferdecker_2019, Galarreta_2023), and the variant has been shown to segregate with disease in related individuals. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31374812, 37144748). One submitter has reported clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV004720277	SCV005329395	likely pathogenic	Peroxisome biogenesis disorder 4A (Zellweger)	2023-05-20	criteria provided, single submitter	clinical testing	The observed missense c.1409G>C(p.Gly470Ala) variant in PEX6 gene has been reported previously in homozygous state in patient(s) affected with Zellweger spectrum disorder (Galarreta CI, et. al., 2022). The p.Gly470Ala variant is absent in gnomAD Exomes database. Multiple lines of computational evidence (Polyphen - probably damaging , SIFT - damaging and MutationTaster - disease causing) predict a damaging effect on protein structure and function for this variant. This variant has been reported to the ClinVar database as Uncertain Significance/ Pathogenic. The amino acid change p.Gly470Ala in PEX6 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Gly at position 470 is changed to a Ala changing protein sequence and it might alter its composition and physico-chemical properties. Functional studies are required to prove pathogenicity of the variant. For these reasons, this variant has been classified as Likely pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV004760722	SCV005373520	uncertain significance	Peroxisome biogenesis disorder 4B	2023-05-20	criteria provided, single submitter	clinical testing	The observed missense c.1409G>C(p.Gly470Ala) variant in PEX6 gene has been reported previously in homozygous state in patient(s) affected with Zellweger spectrum disorder (Galarreta CI, et. al., 2022). The p.Gly470Ala variant is absent in gnomAD Exomes database. This variant has been submitted to the ClinVar database as Uncertain Significance/ Pathogenic. Multiple lines of computational evidence (Polyphen - probably damaging, SIFT - damaging; MutationTaster - disease causing) predict a damaging effect on protein structure and function for this variant. The amino acid change p.Gly470Ala in PEX6 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Gly at position 470 is changed to a Ala changing protein sequence and it might alter its composition and physico-chemical properties. Functional studies are required to prove pathogenicity of the variant. For these reasons, this variant has been classified as Likely pathogenic. The same variant has also been reported in heterozygous state in spouse (Id-30400130013).