Submissions for variant NM_000287.4(PEX6):c.1947del (p.Ile650fs)

dbSNP: rs267608227

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586808	SCV000696485	pathogenic	Peroxisome biogenesis disorder	2016-09-09	criteria provided, single submitter	clinical testing	Variant summary: The PEX6 c.1947delG (p.Ile650Serfs) variant results in a premature termination codon, predicted to cause a truncated or absent PEX6 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 4/121404 control chromosomes at a frequency of 0.0000329, which does not exceed the estimated maximal expected allele frequency of a pathogenic PEX6 variant (0.0019365). The variant has been reported in affected individuals in the literature in the homozygous and heterozygous state. Taken together, this variant is classified as pathogenic.
Eurofins Ntd Llc (ga)	RCV000734107	SCV000862220	pathogenic	not provided	2018-06-29	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000586808	SCV000963976	pathogenic	Peroxisome biogenesis disorder	2024-09-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ile650Serfs*10) in the PEX6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PEX6 are known to be pathogenic (PMID: 10408779, 21031596, 31831025). This variant is present in population databases (rs267608227, gnomAD 0.004%). This premature translational stop signal has been observed in individuals with Zellweger syndrome (PMID: 19142205, 19877282). ClinVar contains an entry for this variant (Variation ID: 495796). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000734107	SCV003824876	pathogenic	not provided	2022-03-15	criteria provided, single submitter	clinical testing
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV003336085	SCV004045814	pathogenic	Peroxisome biogenesis disorder 4A (Zellweger)	2023-09-18	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000734107	SCV004161624	likely pathogenic	not provided	2022-08-01	criteria provided, single submitter	clinical testing	PEX6: PVS1, PS4:Supporting
Baylor Genetics	RCV003471938	SCV004201532	pathogenic	Heimler syndrome 2	2024-03-18	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000665650	SCV005400229	pathogenic	Peroxisome biogenesis disorder 4B	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with peroxisome biogenesis disorder 4B (MIM#614863), Heimler syndrome 2 (MIM#616617) and peroxisome biogenesis disorder 4A (Zellweger; MIM#614862). (I) 0108 - This gene is associated with both recessive and dominant disease. The recurrent variant p.(Arg860Trp) is associated with autosomal dominant peroxisome biogenesis disorder 4B (PMID: 29220678). In addition, Heimler syndrome 2 is milder due to one allele encoding for a protein with residual function (OMIM). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (6 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic, and observed in both homozygous and heterozygous individuals with Zellweger syndrome (PMID: 19877282). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Counsyl	RCV000665650	SCV000789804	pathogenic	Peroxisome biogenesis disorder 4B	2017-02-21	no assertion criteria provided	clinical testing
Natera, Inc.	RCV001834835	SCV002077290	pathogenic	Zellweger spectrum disorders	2020-08-26	no assertion criteria provided	clinical testing