rs61753229
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PS1PM2PM5PP3_ModeratePP5_Very_Strong
The NM_000287.4(PEX6):c.2435G>A(p.Arg812Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000867 in 1,613,976 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R812W) has been classified as Uncertain significance.
Frequency
Consequence
NM_000287.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PEX6 | NM_000287.4 | c.2435G>A | p.Arg812Gln | missense_variant | 13/17 | ENST00000304611.13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PEX6 | ENST00000304611.13 | c.2435G>A | p.Arg812Gln | missense_variant | 13/17 | 1 | NM_000287.4 | P1 | |
PEX6 | ENST00000244546.4 | c.2188G>A | p.Gly730Arg | missense_variant | 11/15 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152184Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251484Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135918
GnomAD4 exome AF: 0.00000889 AC: 13AN: 1461792Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8AN XY: 727208
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152184Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74346
ClinVar
Submissions by phenotype
Peroxisome biogenesis disorder Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 23, 2024 | Variant summary: PEX6 c.2435G>A (p.Arg812Gln) results in a conservative amino acid change located in the AAA+ ATPase domain (IPR003593) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251484 control chromosomes. c.2435G>A has been reported in the literature in individuals affected with Zellweger Syndrome (e.g. Zhang_1999, Ebberink_2010). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and found the variant results in the inability to rescue peroxisome biogenesis activity in deficient cells (Zhang_1999). The following publications have been ascertained in the context of this evaluation (PMID: 19877282, 10408779). ClinVar contains an entry for this variant (Variation ID: 555170). Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 14, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 812 of the PEX6 protein (p.Arg812Gln). This variant is present in population databases (rs61753229, gnomAD 0.02%). This missense change has been observed in individuals with Zellweger syndrome (PMID: 10408779, 19877282). ClinVar contains an entry for this variant (Variation ID: 555170). 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 expected to disrupt PEX6 protein function. Experimental studies have shown that this missense change affects PEX6 function (PMID: 10408779). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Arg812 amino acid residue in PEX6. Other variant(s) that disrupt this residue have been observed in individuals with PEX6-related conditions (PMID: 19877282), 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. - |
Peroxisome biogenesis disorder 4A (Zellweger);C3553937:Peroxisome biogenesis disorder 4B Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Nov 21, 2017 | - - |
Heimler syndrome 2 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 11, 2023 | - - |
Peroxisome biogenesis disorder 1A (Zellweger) Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Center of Genomic medicine, Geneva, University Hospital of Geneva | Mar 05, 2019 | This variant was identified in combination with a second variant in trans in the same gene (PEX6 - composite heterozygosity) in a newborn patient with Zellweger syndrome - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at