rs121909152

chr6-136869905-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000288.4(PEX7):c.649G>A(p.Gly217Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000787 in 1,613,458 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G217E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000081 (0 hom.)
• Consequence: PEX7 NM_000288.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13 O:1
• Conservation: PhyloP100: 7.68

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 16 ACMG points.

• PM1: In a repeat WD 4 (size 31) in uniprot entity PEX7_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_000288.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.946
• PP5: Variant 6-136869905-G-A is Pathogenic according to our data. Variant chr6-136869905-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 7782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-136869905-G-A is described in Lovd as [Pathogenic]. Variant chr6-136869905-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEX7	NM_000288.4	c.649G>A	p.Gly217Arg	missense_variant	7/10	ENST00000318471.5
PEX7	NM_001410945.1	c.535G>A	p.Gly179Arg	missense_variant	7/10
PEX7	XM_006715502.3	c.355G>A	p.Gly119Arg	missense_variant	4/7
PEX7	XM_047418874.1	c.526+23724G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX7	ENST00000318471.5	c.649G>A	p.Gly217Arg	missense_variant	7/10	1	NM_000288.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000358 AC: 9 AN: 251402 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135870

Gnomad AFR exome AF: 0.000123

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: 0.00

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000808 AC: 118 AN: 1461298 Hom.: 0 Cov.: 30 AF XY: 0.0000702 AC XY: 51 AN XY: 726974

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000999

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152160 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74336

Gnomad4 AFR AF: 0.0000241

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: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000995 Hom.: 0

Bravo AF: 0.0000869

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rhizomelic chondrodysplasia punctata type 1 Pathogenic:5 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 1997	- -
Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Mar 04, 2016	c.649G>A, p.Gly217Arg variant has previously been reported in trans with a known pathogenic variant, p.Leu292ter in five affected individuals (Braverman N et al., 1997) as well as in the homozygous state in one affected individual (Braverman et al. 2002). It has been shown to induce an import defect where the protein remains mainly cytosolic instead of targeting to the peroxisome (Braverman et al. 2002). In 138 affected individuals, this variant has been observed in 10 alleles (~4%) (Braverman et al. 2002; Motley AM et al., 2002); in the ExAC database, only 2 alleles with this variant has been reported (0.002%). This indicates that the prevalence of this variant is significantly higher in cases compared with controls (Odds ratio 2282; 95% CI 498 – 10466). Multiple in silico algorithms predict a deleterious effect (GERP =4.98; CADD = 19.87; PolyPhen = 1; SIFT = 0). Therefore, this collective evidence supports the classification of the c.649G>A (p.Gly217Arg) as a Pathogenic variant for rhizomelic chondrodysplasia punctata type I. We have confirmed this finding in our laboratory using Sanger sequencing. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 11, 2019	NM_000288.3(PEX7):c.649G>A(G217R) is classified as likely pathogenic in the context of type 1 rhizomelic chondrodysplasia punctata. Sources cited for classification include the following: PMID 11781871, 12325024, and 11756410. Classification of NM_000288.3(PEX7):c.649G>A(G217R) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 24, 2018	Variant summary: PEX7 c.649G>A (p.Gly217Arg) results in a non-conservative amino acid change located in the WD40-repeat-containing domain of 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-05 in 277138 control chromosomes (gnomAD). c.649G>A has been reported in the literature in multiple individuals affected with Rhizomelic Chondrodysplasia Punctata Type 1 (Braverman_1997, Motley_2002). These data indicate that the variant is very likely to be associated with disease. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Motley_2002). Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 31, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 31, 2021	Published functional studies demonstrate a damaging effect due to abnormal cellular localization restricted to the cytosol and impaired protein binding (Braverman et al., 2002; Mukai et al., 2002); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 12325024, 11756410, 24172221, 9090381, 20301447, 9472033, 10083738, 12054588, 15287046, 11781871, 23572185, 20145307) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 13, 2020	PS3, PS4, PM2, PP3 -

Peroxisome biogenesis disorder 9B Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Mar 04, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 22, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 05, 2024	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 217 of the PEX7 protein (p.Gly217Arg). This variant is present in population databases (rs121909152, gnomAD 0.01%). This missense change has been observed in individuals with rhizomelic chondrodysplasia punctata (PMID: 9090381, 11781871, 12325024, 23572185). ClinVar contains an entry for this variant (Variation ID: 7782). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects PEX7 function (PMID: 9472033, 11756410, 12325024). For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 17, 2021

The c.649G>A (p.G217R) alteration is located in exon 7 (coding exon 7) of the PEX7 gene. This alteration results from a G to A substitution at nucleotide position 649, causing the glycine (G) at amino acid position 217 to be replaced by an arginine (R). Based on data from gnomAD, the A allele has an overall frequency of 0.004% (11/282,804) total alleles studied. The highest observed frequency was 0.01% (3/24,972) of African alleles. This alteration has been reported compound heterozygous with a second alteration in PEX7 in multiple patients with rhizomelic chondrodysplasia punctata (RCDP) (Braverman, 1997; Braverman, 2002). Motley et al. (2002) also reported this alteration in patients with RCDP. This amino acid position is highly conserved in available vertebrate species. Functional studies showed that this alteration resulted in abnormal cellular localization and defective protein binding in Chinese hamster ovary ZPG207 mutant cells and fibroblasts from patients with RCDP (Braverman, 2002; Mukai, 2002). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Rhizomelic chondrodysplasia punctata Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Feb 25, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.32
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Pathogenic	3.3	M;M
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-6.5	D;D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	.;D
Vest4		0.99
MutPred		0.95		Gain of MoRF binding (P = 0.054);Gain of MoRF binding (P = 0.054);
MVP		0.96
MPC		0.27
ClinPred		0.95	D
GERP RS		5.0
Varity_R		0.79
gMVP		0.87

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: rs121909152; hg19: chr6-137191043; COSMIC: COSV59247739;