Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Institute of Medical Genetics and Applied Genomics, |
RCV001268007 | SCV001446580 | likely pathogenic | not provided | 2020-10-23 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001420823 | SCV001623208 | likely pathogenic | PMM2-congenital disorder of glycosylation | 2021-04-28 | criteria provided, single submitter | clinical testing | Variant summary: PMM2 c.255G>A (p.Gln85Gln) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a 5' donor site. One predicts the variant abolishes a 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing and results in exon 3 skipping (LeBizec_2005). The variant allele was found at a frequency of 8e-06 in 251450 control chromosomes (gnomAD and publication data). c.255G>A has been reported in the literature in one individual affected with Congenital Disorder Of Glycosylation Type 1a (LeBizec_2005). These data do not allow any conclusion about variant significance. One ClinVar submitter (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Labcorp Genetics |
RCV001420823 | SCV003443483 | uncertain significance | PMM2-congenital disorder of glycosylation | 2022-03-20 | criteria provided, single submitter | clinical testing | This sequence change affects codon 85 of the PMM2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PMM2 protein. This variant also falls at the last nucleotide of exon 3, which is part of the consensus splice site for this exon. This variant is present in population databases (rs115344041, gnomAD 0.0009%). This variant has been observed in individual(s) with congenital disorder of glycosylation type Ia (PMID: 15844218). ClinVar contains an entry for this variant (Variation ID: 986866). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. |
| Gene |
RCV001268007 | SCV003803458 | likely pathogenic | not provided | 2022-08-05 | criteria provided, single submitter | clinical testing | Alters the last nucleotide of the exon and results in aberrant splicing with skipping of exon 3 (Le Bizec et al., 2005); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15844218, 34277356) |
| Baylor Genetics | RCV001420823 | SCV005056367 | likely pathogenic | PMM2-congenital disorder of glycosylation | 2024-02-20 | criteria provided, single submitter | clinical testing |