ClinVar Miner

Submissions for variant NM_000288.4(PEX7):c.649G>A (p.Gly217Arg)

gnomAD frequency: 0.00005  dbSNP: rs121909152
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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000008224 SCV000223941 pathogenic Rhizomelic chondrodysplasia punctata type 1 2016-03-04 criteria provided, single submitter clinical testing 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000008224 SCV000919983 pathogenic Rhizomelic chondrodysplasia punctata type 1 2018-07-24 criteria provided, single submitter clinical testing 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.
Invitae RCV000454287 SCV000959891 pathogenic Peroxisome biogenesis disorder 9B 2024-01-05 criteria provided, single submitter clinical testing 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.
Baylor Genetics RCV000008224 SCV001163000 pathogenic Rhizomelic chondrodysplasia punctata type 1 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV000008224 SCV001193971 likely pathogenic Rhizomelic chondrodysplasia punctata type 1 2019-12-11 criteria provided, single submitter clinical testing 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.
Mayo Clinic Laboratories, Mayo Clinic RCV001509294 SCV001715916 pathogenic not provided 2020-07-13 criteria provided, single submitter clinical testing PS3, PS4, PM2, PP3
GeneDx RCV001509294 SCV001873946 pathogenic not provided 2021-08-31 criteria provided, single submitter clinical testing 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)
Revvity Omics, Revvity Omics RCV001509294 SCV002018764 pathogenic not provided 2020-07-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV002512897 SCV003562225 pathogenic Inborn genetic diseases 2021-11-17 criteria provided, single submitter clinical testing 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.
Baylor Genetics RCV000454287 SCV004201630 pathogenic Peroxisome biogenesis disorder 9B 2023-10-22 criteria provided, single submitter clinical testing
OMIM RCV000008224 SCV000028431 pathogenic Rhizomelic chondrodysplasia punctata type 1 1997-04-01 no assertion criteria provided literature only
GeneReviews RCV000008224 SCV000055659 not provided Rhizomelic chondrodysplasia punctata type 1 no assertion provided literature only
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000454287 SCV000538054 pathogenic Peroxisome biogenesis disorder 9B 2016-03-04 no assertion criteria provided clinical testing
Natera, Inc. RCV001831556 SCV002077247 pathogenic Rhizomelic chondrodysplasia punctata 2020-02-25 no assertion criteria provided clinical testing

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