chr6-42965115-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_000287.4(PEX6):c.2626C>T(p.Arg876Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000991 in 1,614,082 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R876Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_000287.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PEX6 | NM_000287.4 | c.2626C>T | p.Arg876Trp | missense_variant | 15/17 | ENST00000304611.13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PEX6 | ENST00000304611.13 | c.2626C>T | p.Arg876Trp | missense_variant | 15/17 | 1 | NM_000287.4 | P1 | |
PEX6 | ENST00000244546.4 | c.*162C>T | 3_prime_UTR_variant | 13/15 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152206Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251444Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135888
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461876Hom.: 0 Cov.: 33 AF XY: 0.0000124 AC XY: 9AN XY: 727234
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152206Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74354
ClinVar
Submissions by phenotype
Peroxisome biogenesis disorder Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 12, 2022 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 876 of the PEX6 protein (p.Arg876Trp). This variant is present in population databases (rs267608246, gnomAD 0.0009%). This missense change has been observed in individual(s) with an autosomal recessive Zellweger syndrome spectrum disorder (PMID: 19877282). ClinVar contains an entry for this variant (Variation ID: 551183). 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: "Probably Damaging"; Align-GVGD: "Class C0"). 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 12, 2023 | Variant summary: PEX6 c.2626C>T (p.Arg876Trp) 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 4e-06 in 251444 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2626C>T has been reported in the literature in homozygous individuals and compound heterozygotes, who carried a null allele in trans, and all were affected with a milder form of Zellweger Syndrome, including symptoms of retinal dystrophy and hearing loss (Ebberink_2010, Witters_2016, Perea-Romero_2021, Biswas_2021), suggesting that the variant might cause only a partial loss of PEX6 function. 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. Five ClinVar submitters (evaluation after 2014) have cited the variant, and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
PEX6-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 05, 2024 | The PEX6 c.2626C>T variant is predicted to result in the amino acid substitution p.Arg876Trp. This variant was reported in the compound heterozygous state in an individual with suspected Zellweger syndrome (Witters et al. 2016. PubMed ID: 27007981; Ebberink et al. 2010. PubMed ID: 19877282). This variant was also reported, along with a protein-truncating variant in the same gene, in an individual who presented with retinitis pigmentosa and hearing loss (Perea-Romero et al. 2021. PubMed ID: 34448047). Lastly, this variant was described in the homozygous state in an individual with retinal dystrophy (Biswas et al. 2021. PubMed ID: 34662339). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Although we suspect that c.2626C>T (p.Arg876Trp) may be pathogenic, the clinical significance of this variant is currently classified as uncertain at this time due to the absence of conclusive functional and genetic evidence. - |
Peroxisome biogenesis disorder 4A (Zellweger);C3553937:Peroxisome biogenesis disorder 4B Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Mar 20, 2017 | - - |
Peroxisome biogenesis disorder 4A (Zellweger);C3553937:Peroxisome biogenesis disorder 4B;C4225267:Heimler syndrome 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 07, 2022 | - - |
Peroxisome biogenesis disorder 4A (Zellweger) Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Mar 19, 2020 | This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PM3,PP3. - |
Heimler syndrome 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 28, 2022 | - - |
Zellweger spectrum disorders Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 11, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at