ClinVar Miner

Submissions for variant NM_000303.3(PMM2):c.359T>C (p.Ile120Thr)

gnomAD frequency: 0.00006  dbSNP: rs368582085
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000670926 SCV000795847 likely pathogenic PMM2-congenital disorder of glycosylation 2017-11-21 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000670926 SCV000950807 pathogenic PMM2-congenital disorder of glycosylation 2024-01-17 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 120 of the PMM2 protein (p.Ile120Thr). This variant is present in population databases (rs368582085, gnomAD 0.03%). This missense change has been observed in individuals with PMM2-CDG (PMID: 17308246, 28425223). ClinVar contains an entry for this variant (Variation ID: 555161). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PMM2 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000670926 SCV003800715 likely pathogenic PMM2-congenital disorder of glycosylation 2023-01-18 criteria provided, single submitter clinical testing Variant summary: PMM2 c.359T>C (p.Ile120Thr) results in a non-conservative amino acid change in 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 8.6e-05 in 185580 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in PMM2 causing Congenital Disorder Of Glycosylation Type 1a (8.6e-05 vs 0.0056), allowing no conclusion about variant significance. c.359T>C has been reported in the literature in the compound heterozygous state in three unrelated individuals affected with Congenital Disorder Of Glycosylation Type 1a (CDG-Ia) and in at least one other individual wherein the presence or absence of a second variant was not indicated (e.g. Matthijs_2000, Dinopoulos_2007, Coorg_2012, Vals_2017). These data indicate that the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either VUS (n=2) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
PreventionGenetics, part of Exact Sciences RCV003424274 SCV004118372 likely pathogenic PMM2-related disorder 2023-05-17 criteria provided, single submitter clinical testing The PMM2 c.359T>C variant is predicted to result in the amino acid substitution p.Ile120Thr. This variant was reported, along with a second pathogenic variant, in a patient who presented with mild CDG (Vals et al. 2017. PubMed ID: 28425223). This variant was also reported in two other individuals who presented with CDG type Ia; at least one of these individuals also harbored a second known pathogenic variant (Dinopoulos et al. 2007. PubMed ID: 17308246; Matthijs et al. 2000. PubMed ID: 11058895). This variant is reported in 0.028% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-8904947-T-C). This variant is interpreted as likely pathogenic.
Baylor Genetics RCV000670926 SCV004204838 pathogenic PMM2-congenital disorder of glycosylation 2024-03-28 criteria provided, single submitter clinical testing
Natera, Inc. RCV000670926 SCV002089476 uncertain significance PMM2-congenital disorder of glycosylation 2020-02-26 no assertion criteria provided clinical testing

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