ClinVar Miner

Submissions for variant NM_000288.3(PEX7):c.649G>A (p.Gly217Arg) (rs121909152)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000008224 SCV000678149 likely pathogenic Rhizomelic chondrodysplasia punctata type 1 2015-06-14 criteria provided, single submitter clinical testing
GeneReviews RCV000008224 SCV000055659 pathologic Rhizomelic chondrodysplasia punctata type 1 2012-09-13 no assertion criteria provided curation Converted during submission to Pathogenic.
Integrated Genetics/Laboratory Corporation of America 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.
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.
Knight Diagnostic Laboratories,Oregon Health and Sciences University RCV000454287 SCV000538054 pathogenic Peroxisome biogenesis disorder 9B 2016-03-04 criteria provided, single submitter clinical testing
OMIM RCV000008224 SCV000028431 pathogenic Rhizomelic chondrodysplasia punctata type 1 1997-04-01 no assertion criteria provided literature only

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