Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Hudson |
RCV000850396 | SCV000992591 | likely pathogenic | PMM2-congenital disorder of glycosylation | 2019-07-03 | criteria provided, single submitter | research | |
Labcorp Genetics |
RCV000850396 | SCV001558414 | uncertain significance | PMM2-congenital disorder of glycosylation | 2021-09-08 | criteria provided, single submitter | clinical testing | This sequence change replaces proline with serine at codon 20 of the PMM2 protein (p.Pro20Ser). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and serine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with PMM2-congenital disorder of glycosylation (CDG-Ia) (PMID: 15844218, 20638314). ClinVar contains an entry for this variant (Variation ID: 689645). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV002265902 | SCV002547964 | uncertain significance | not specified | 2022-05-26 | criteria provided, single submitter | clinical testing | Variant summary: PMM2 c.58C>T (p.Pro20Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.3e-05 in 228314 control chromosomes. c.58C>T has been reported in the literature in as a compound heterozygous genotype with c.395T>C (p.Ile132Thr) on the other allele in at-least one individual affected with Congenital Disorder Of Glycosylation Type 1a (example, Le Bizec_2005 cited in Monin_2014). These report(s) do not provide unequivocal conclusions about association of the variant with Congenital Disorder Of Glycosylation Type 1a. A co-occurrence in cis with another pathogenic variant(s) has been reported in the individual described above (Le Bizec_2005) and observed at our laboratory (PMM2 c.66+1G>T), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function for this variant in isolation as expressed in an E Coli system (Li Bizec_2005). The most pronounced variant effect results in approximately 20% of normal PMM2 activity in vitro. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Likely pathogenic, n=1; VUS, n=2). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |
Gene |
RCV004789237 | SCV005402070 | likely pathogenic | not provided | 2024-05-16 | criteria provided, single submitter | clinical testing | Observed with the c.66+1 G>T variant on the same allele (in cis) as well as another pathogenic variant on the opposite allele (in trans) in patients with features of a congenital disorder of glycosylation in published literature (PMID: 15844218, 20638314, 25497157); Published functional studies demonstrate a damaging effect with decreased enzyme activity (PMID: 15844218); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31420886, 34859900, 34277356, 20638314, 33209585, 25497157, 15844218) |
Natera, |
RCV000850396 | SCV002089461 | uncertain significance | PMM2-congenital disorder of glycosylation | 2020-10-13 | no assertion criteria provided | clinical testing |