rs1805137

Positions:

• chr6-136898213-T-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000288.4(PEX7):​c.875T>A​(p.Leu292Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.000683 in 1,609,616 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L292L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00071 (0 hom.)
• Consequence: PEX7 NM_000288.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:26 O:1
• Conservation: PhyloP100: 6.12

Genes affected

PEX7 (HGNC:8860): (peroxisomal biogenesis factor 7) This gene encodes the cytosolic receptor for the set of peroxisomal matrix enzymes targeted to the organelle by the peroxisome targeting signal 2 (PTS2). Defects in this gene cause peroxisome biogenesis disorders (PBDs), which are characterized by multiple defects in peroxisome function. There are at least 14 complementation groups for PBDs, with more than one phenotype being observed in cases falling into particular complementation groups. Although the clinical features of PBD patients vary, cells from all PBD patients exhibit a defect in the import of one or more classes of peroxisomal matrix proteins into the organelle. Defects in this gene have been associated with PBD complementation group 11 (PBD-CG11) disorders, rhizomelic chondrodysplasia punctata type 1 (RCDP1), and Refsum disease (RD). [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 6 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-136898213-T-A is Pathogenic according to our data. Variant chr6-136898213-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 7780.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-136898213-T-A is described in Lovd as [Likely_pathogenic]. Variant chr6-136898213-T-A is described in Lovd as [Pathogenic]. Variant chr6-136898213-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEX7	NM_000288.4	c.875T>A	p.Leu292Ter	stop_gained	9/10	ENST00000318471.5
PEX7	NM_001410945.1	c.761T>A	p.Leu254Ter	stop_gained	9/10
PEX7	XM_006715502.3	c.581T>A	p.Leu194Ter	stop_gained	6/7
PEX7	XM_047418874.1	c.598T>A	p.Ter200LysextTer?	stop_lost	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX7	ENST00000318471.5	c.875T>A	p.Leu292Ter	stop_gained	9/10	1	NM_000288.4	P1

Frequencies

GnomAD3 genomes AF: 0.000447 AC: 68 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000867

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000326 AC: 82 AN: 251304 Hom.: 0 AF XY: 0.000302 AC XY: 41 AN XY: 135812

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000669

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000708 AC: 1032 AN: 1457426 Hom.: 0 Cov.: 28 AF XY: 0.000682 AC XY: 495 AN XY: 725374

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.000890

Gnomad4 OTH exome AF: 0.000564

GnomAD4 genome AF: 0.000447 AC: 68 AN: 152190 Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74364

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000867

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000650 Hom.: 0

Bravo AF: 0.000374

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000247 AC: 30

EpiCase AF: 0.000872

EpiControl AF: 0.000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:26 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:12

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 07, 2019	The PEX7 c.875T>A; p.Leu292Ter variant (rs1805137) accounts for about 50% of disease alleles in individuals affected with rhizomelic chondrodysplasia punctata type 1, and is reported in the literature in many affected individuals in the homozygous and compound heterozygous state (Braverman 1997, Braverman 2000, Jacobsen 2015, Motley 2002). This variant is reported in ClinVar (Variation ID: 7780), and is found in the general population with an overall allele frequency of 0.034% (96/282696 alleles) in the Genome Aggregation Database. This variant induces an early termination codon and is predicted to result in a truncated protein, since functional analyses of the variant protein show normal expression but a loss of function due to an inability to bind to the PTS2 ligand (Braverman 1997, Mukai 2002). Based on available information, this variant is considered to be pathogenic. References: Braverman et al. Human PEX7 encodes the peroxisomal PTS2 receptor and is responsible for rhizomelic chondrodysplasia punctata. Nat Genet. 1997 Apr;15(4):369-76. Braverman N et al. PEX7 gene structure, alternative transcripts, and evidence for a founder haplotype for the frequent RCDP allele, L292ter. Genomics. 2000 Jan 15;63(2):181-92. Jacobsen JC et al. Whole Exome Sequencing Reveals Compound Heterozygosity for Ethnically Distinct PEX7 Mutations Responsible for Rhizomelic Chondrodysplasia Punctata, Type 1. Case Rep Genet. 2015;2015:454526. Motley AM et al. Mutational spectrum in the PEX7 gene and functional analysis of mutant alleles in 78 patients with rhizomelic chondrodysplasia punctata type 1. Am J Hum Genet. 2002 Mar;70(3):612-24. Mukai S et al. Intracellular localization, function, and dysfunction of the peroxisome-targeting signal type 2 receptor, Pex7p, in mammalian cells. J Biol Chem. 2002 Mar 15;277(11):9548-61. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 25, 2018	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2022	Nonsense variant in the C-terminus predicted to result in protein truncation of the last 32 amino acids; In vitro functional studies of p.(L292*) demonstrate impaired binding of essential protein and reduced protein function (Mukai et al., 2002); This variant is associated with the following publications: (PMID: 30487145, 10083738, 25525159, 9090381, 28555434, 26587300, 11781871, 31980526, 31589614, 23572185, 21990100, 9090382, 11756410, 35055178) -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Mar 16, 2021	PVS1, PS3, PM3 -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 19, 2022	- -

Rhizomelic chondrodysplasia punctata type 1 Pathogenic:8 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 10, 2014	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 08, 2016	Variant summary: The PEX7 c.875T>A (p.Leu292X) variant results in a premature termination codon, predicted to cause a truncated or absent PEX7 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant of interest has been indicated to be a known founder mutation arising from an ancestral chromosome in the Caucasian population per Braverman_2000. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 30/121346 (1/4045), which does not exceed the estimated maximal expected allele frequency for a pathogenic PEX7 variant of 1/534. The variant of interest has been reported in multiple affected individuals in a homozygous and compound heterozygous state. In addition, multiple reputable clinical diagnostic laboratories/databases cite the variant as "pathogenic." Therefore, the variant of interest has been classified as "pathogenic." -
Pathogenic, criteria provided, single submitter	clinical testing	Courtagen Diagnostics Laboratory, Courtagen Life Sciences	Nov 11, 2014	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 12, 2019	NM_000288.3(PEX7):c.875T>A(L292*) is classified as pathogenic in the context of type 1 rhizomelic chondrodysplasia punctata. Sources cited for classification include the following: PMID 9090383, 21465523, 10673331, 12325024, 11781871 and 9090381. Classification of NM_000288.3(PEX7):c.875T>A(L292*) is based on the following criteria: The variant causes a premature termination codon that is not expected to be targeted by nonsense-mediated mRNA decay; however, literature evidence strongly supports pathogenicity. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 19, 2020	Based on the classification scheme VCGS_Germline_v1.3.2, 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 rhizomelic chondrodysplasia punctata, type 1. (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (96 heterozygotes, 0 homozygotes). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported as pathogenic in many patients with rhizomelic chondrodysplasia punctata, and is considered to be a founder variant in the European population (ClinVar, HGMD, PMID: 9090381, PMID: 20301447). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies in transfected cells showed impaired protein function (PMID: 9090381). (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (VCGS #20G001699 and 20G001700). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

PEX7-related disorder Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Oct 27, 2023	The PEX7 c.875T>A variant is predicted to result in premature protein termination (p.Leu292*). This variant is reported to be one of the most common pathogenic variants identified in rhizomelic chondrodysplasia punctata patients (Braverman et al. 1997. PubMed ID: 9090381; Motley et al. 2002. PubMed ID: 11781871; Shimozawa et al. 1999. PubMed ID: 10083738). This variant is reported in 0.068% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/6-137219351-T-A). Nonsense variants in PEX7 are expected to be pathogenic. This variant is interpreted as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The PEX7 c.875T>A (p.Leu292Ter) variant is a stop-gained variant that is well described as a pathogenic variant, accounting for 51% of disease alleles in individuals with rhizomelic chondrodysplasia punctata (Bravermann et al. 2012). The p.Leu292Ter variant is described in at least ten studies and found in a total of at least 187 individuals including 107 in a homozygous state, 47 in a compound heterozygous state, and 33 individuals in a heterozygous state (Braverman et al. 1997; Motley et al. 1997; Purdue et al. 1997; Brites et al. 1998; Shimozawa et al. 1999; Braverman et al. 2000; Motley et al. 2002; Braverman et al. 2002; Huffnagel et al. 2013; Jacobsen et al. 2016). The variant was absent from 41 controls but is reported at a frequency of 0.00058 in the European American population of the Exome Sequencing Project. The high frequency of the p.Leu292Ter allele is secondary to a founder effect in individuals of Northern European descent. Functional studies showed that the p.Leu292Ter variant protein is localized to the peroxisomes in contrast to the cystolic location of the wild type protein (Bravermann et al. 2012). The variant protein was also shown to be inactive in restoring defective PTS2 import in fibroblasts from patients and Chinese hamster ovary cells and to be impaired in binding both PST2 and PEX5 (Motley et al. 1997; Purdue et al. 1997; Mukai et al. 2002). Based on the collective evidence and the potential impact of stop-gained variants, the p.Leu292Ter variant is classified as pathogenic for PEX7-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Peroxisome biogenesis disorder 9B Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	This sequence change creates a premature translational stop signal (p.Leu292*) in the PEX7 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 32 amino acid(s) of the PEX7 protein. This variant is present in population databases (rs1805137, gnomAD 0.07%). This premature translational stop signal has been observed in individuals with rhizomelic chondrodysplasia punctata (PMID: 9090381, 9090382, 10083738, 21990100, 22008564, 23572185, 25800479). It is commonly reported in individuals of Northern European ancestry (PMID: 9090381, 9090382, 10083738, 21990100, 22008564, 23572185, 25800479). ClinVar contains an entry for this variant (Variation ID: 7780). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects PEX7 function (PMID: 9090381, 9090382, 11756410). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 27, 2024	- -

Rhizomelic chondrodysplasia punctata type 1;C2749346:Peroxisome biogenesis disorder 9B Pathogenic:1

Pathogenic, no assertion criteria provided

research

Division of Human Genetics, Children's Hospital of Philadelphia

Aug 16, 2016

- -

Phytanic acid storage disease;C1859133:Rhizomelic chondrodysplasia punctata type 1;C2749346:Peroxisome biogenesis disorder 9B Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 03, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	38
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Uncertain	0.95	D
MutationTaster	Benign	1.0	A;A
Vest4		0.92
GERP RS		5.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1805137; hg19: chr6-137219351;