ClinVar Miner

Submissions for variant NM_000288.4(PEX7):c.653C>T (p.Ala218Val) (rs121909151)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000032925 SCV000776819 pathogenic Peroxisome biogenesis disorder 9B 2020-10-06 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 218 of the PEX7 protein (p.Ala218Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs121909151, ExAC 0.003%). This variant has been reported as homozygous or in combination with another PEX7 variant in several individuals affected with rhizomelic chondrodysplasia punctata (PMID: 9090381, 10083738, 12325024, 11781871). ClinVar contains an entry for this variant (Variation ID: 7781). Experimental studies have shown that this missense change reduces binding to both PTS2 and PEX5pL resulting in impairment of peroxisomal import of PTS2 (PMID: 11756410, 11781871). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000008223 SCV001163001 pathogenic Rhizomelic chondrodysplasia punctata type 1 criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000008223 SCV001193850 likely pathogenic Rhizomelic chondrodysplasia punctata type 1 2019-12-09 criteria provided, single submitter clinical testing NM_000288.3(PEX7):c.653C>T(A218V) is classified as likely pathogenic in the context of rhizomelic chondrodysplasia punctata type 1. Sources cited for classification include the following: PMID 12325024, 9090382, 9090381 and 11756410. Classification of NM_000288.3(PEX7):c.653C>T(A218V) 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000008223 SCV001442684 pathogenic Rhizomelic chondrodysplasia punctata type 1 2020-10-04 criteria provided, single submitter clinical testing Variant summary: PEX7 c.653C>T (p.Ala218Val) results in a non-conservative amino acid change located in the WD40-repeat-containing domain (IPR017986) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251372 control chromosomes. c.653C>T has been reported in the literature in multiple individuals affected with Rhizomelic Chondrodysplasia Punctata Type (example, Braverman_1997, Shimozawa_1999, Braverman_2002, Motley_2002). These data indicate that the variant is very likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in impaired transport of PTS2 (peroxisome-targeting signal type 2 (PTS2) nonapeptide sequence) signal containing proteins into the peroxisomes (Braverman_1997, Mukai_2002). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx RCV000656252 SCV001781986 pathogenic not provided 2021-01-28 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 12325024, 10083738, 11756410, 9090381, 11781871)
OMIM RCV000008223 SCV000028430 pathogenic Rhizomelic chondrodysplasia punctata type 1 1997-04-01 no assertion criteria provided literature only
GeneReviews RCV000008223 SCV000055660 pathologic Rhizomelic chondrodysplasia punctata type 1 2012-09-13 no assertion criteria provided curation Converted during submission to Pathogenic.
OMIM RCV000032925 SCV000056697 pathogenic Peroxisome biogenesis disorder 9B 1997-04-01 no assertion criteria provided literature only
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes RCV000656252 SCV000778213 pathogenic not provided 2016-08-26 no assertion criteria provided clinical testing

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