Submissions for variant NM_000287.4(PEX6):c.821C>T (p.Pro274Leu)

gnomAD frequency: 0.00003  dbSNP: rs61753219

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000622824	SCV000741077	pathogenic	Inborn genetic diseases	2015-10-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000666553	SCV000790861	likely pathogenic	Peroxisome biogenesis disorder 4A (Zellweger); Peroxisome biogenesis disorder 4B	2017-04-12	criteria provided, single submitter	clinical testing
Undiagnosed Diseases Network, NIH	RCV000735222	SCV000863430	likely pathogenic	Peroxisome biogenesis disorder 4B	2018-09-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193476	SCV001362344	pathogenic	Peroxisome biogenesis disorder	2019-07-11	criteria provided, single submitter	clinical testing	Variant summary: PEX6 c.821C>T (p.Pro274Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251460 control chromosomes. c.821C>T has been reported in the literature in multiple individuals affected with Zellweger Syndrome (Steinberg_2004,Ebberink_2010) and Heimler Syndrome (Ratbi_2015). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function (Ratbi_2015, Falkenberg_2017). The most pronounced variant effect results in <10% of normal peroxisomal activity. Four ClinVar submissions (evaluation after 2014) cite the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001193476	SCV001372601	pathogenic	Peroxisome biogenesis disorder	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 274 of the PEX6 protein (p.Pro274Leu). This variant is present in population databases (rs61753219, gnomAD 0.008%). This missense change has been observed in individual(s) with Zellweger Syndrome Spectrum (PMID: 15542397, 19877282, 24016303, 26387595). 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: 217424). 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. Experimental studies have shown that this missense change affects PEX6 function (PMID: 26387595, 29220678). For these reasons, this variant has been classified as Pathogenic.
Centogene AG - the Rare Disease Company	RCV001808558	SCV002059805	pathogenic	Peroxisome biogenesis disorder 4A (Zellweger)	2019-06-20	criteria provided, single submitter	clinical testing
GeneDx	RCV002243878	SCV002512893	pathogenic	not provided	2021-07-26	criteria provided, single submitter	clinical testing	Complementation assays demonstrate P274L could only minimally complement peroxisomal biogenesis, indicating P274L protein is functionally defective (Ratbi et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26387595, 24016303, 19877282, 15542397, 20872098, 19105186)
Baylor Genetics	RCV000201297	SCV004201536	pathogenic	Heimler syndrome 2	2024-03-26	criteria provided, single submitter	clinical testing
OMIM	RCV000201297	SCV000256084	pathogenic	Heimler syndrome 2	2015-10-01	no assertion criteria provided	literature only
Natera, Inc.	RCV001276623	SCV001463075	pathogenic	Zellweger spectrum disorders	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004737319	SCV005346924	pathogenic	PEX6-related disorder	2024-06-11	no assertion criteria provided	clinical testing	The PEX6 c.821C>T variant is predicted to result in the amino acid substitution p.Pro274Leu. This variant has been reported in the homozygous and compound heterozygous state in individuals with peroxisome biogenesis disorder (Table 4, Steinberg et al. 2004. PubMed ID: 15542397; Table 2, Ratbi et al. 2015. PubMed ID: 26387595; Table 1, Yik et al. 2009. PubMed ID: 19105186; Supplemental Table 2, Ebberink et al. 2010. PubMed ID: 19877282). This variant is reported in 0.0079% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.