ClinVar Miner

Submissions for variant NM_000303.3(PMM2):c.484C>T (p.Arg162Trp) (rs104894526)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000008148 SCV000220327 likely pathogenic Carbohydrate-deficient glycoprotein syndrome type I 2014-05-16 criteria provided, single submitter literature only
GeneDx RCV000403363 SCV000329703 pathogenic not provided 2015-12-31 criteria provided, single submitter clinical testing The R162W pathogenic variant in the PMM2 gene has been reported previously in the compound heterozygous state, opposite of a second PMM2 pathogenic variant in many patients with congenital disorder of glycosylation, type 1a, more recently known as PMM2-CDG (Quelhas et al., 2007; Matthijs et al., 1997; Perez et al., 2011). The R162W variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R162W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved. Functional studies demonstrate the R162W variant protein is less stable than the wild type and has reduced enzyme activity (Yuste-Checa et al., 2015). We interpret R162W as a pathogenic variant.
Invitae RCV000008148 SCV000829571 pathogenic Carbohydrate-deficient glycoprotein syndrome type I 2018-12-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 162 of the PMM2 protein (p.Arg162Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs104894526, ExAC 0.006%). This variant has been observed in the compound-heterozygous state in several individuals affected with congenital disorder of glycosylation type 1a (PMID: 9140401, 17166182, 9497260, 21541725, 15844218). ClinVar contains an entry for this variant (Variation ID: 7709). Experimental studies have shown that this missense change impairs protein stability and enzyme activity (PMID: 26014514, 10386614). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000008148 SCV000028353 pathogenic Carbohydrate-deficient glycoprotein syndrome type I 1997-05-01 no assertion criteria provided literature only
SIB Swiss Institute of Bioinformatics RCV000008148 SCV000803453 likely pathogenic Carbohydrate-deficient glycoprotein syndrome type I 2018-05-31 criteria provided, single submitter curation This variant is interpreted as a Likely Pathogenic, for Congenital disorder of glycosylation, type Ia, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PM3 => For recessive disorders, detected in trans with a pathogenic variant (PMID:21541725). PS3 => Well-established functional studies show a deleterious effect (PMID:21541725,10386614).

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