ClinVar Miner

Submissions for variant NM_000287.4(PEX6):c.2735C>T (p.Ala912Val)

gnomAD frequency: 0.00003  dbSNP: rs62641232
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001049060 SCV001213094 pathogenic Peroxisome biogenesis disorder 2024-01-22 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 912 of the PEX6 protein (p.Ala912Val). This variant is present in population databases (rs62641232, gnomAD 0.002%). This missense change has been observed in individual(s) with Zellweger syndrome (PMID: 26669662, 27779215). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 845895). 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 with a positive predictive value of 95%. This variant disrupts the p.Ala912 amino acid residue in PEX6. Other variant(s) that disrupt this residue have been observed in individuals with PEX6-related conditions (PMID: 27604308), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine RCV001823180 SCV002073036 likely pathogenic Peroxisome biogenesis disorder 4A (Zellweger) criteria provided, single submitter clinical testing The missense variant p.A912V in PEX6 (NM_000287.4) has been reported previously in individual(s) with Zellweger syndrome (Guissart C et al; Wang X et al ). The variant has been submitted to ClinVar as Likely Pathogenic. The p.A912V variant is observed in 1/1,13,724 (0.0009%) alleles from individuals of European (Non-Finnish) background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.A912V missense variant is predicted to be damaging by both SIFT and PolyPhen2. The alanine residue at codon 912 of PEX6 is conserved in all mammalian species. The nucleotide c.2735 in PEX6 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic.
Fulgent Genetics, Fulgent Genetics RCV002479299 SCV002783753 likely pathogenic Peroxisome biogenesis disorder 4A (Zellweger); Peroxisome biogenesis disorder 4B; Heimler syndrome 2 2021-07-23 criteria provided, single submitter clinical testing
Center for Personalized Medicine, Children's Hospital Los Angeles RCV003156137 SCV003845303 likely pathogenic See cases 2022-12-21 criteria provided, single submitter clinical testing
Baylor Genetics RCV003473637 SCV004201529 pathogenic Heimler syndrome 2 2023-10-10 criteria provided, single submitter clinical testing
Natera, Inc. RCV001274622 SCV001458947 likely pathogenic Zellweger spectrum disorders 2020-09-16 no assertion criteria provided clinical testing

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