ClinVar Miner

Submissions for variant NM_002435.3(MPI):c.1193T>C (p.Ile398Thr)

gnomAD frequency: 0.00003  dbSNP: rs369326210
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001067096 SCV001232132 pathogenic MPI-congenital disorder of glycosylation 2023-10-31 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 398 of the MPI protein (p.Ile398Thr). This variant is present in population databases (rs369326210, gnomAD 0.008%). This missense change has been observed in individual(s) with MPI-congenital disorder of glycosylation (CDG-Ib) (PMID: 10484808, 30545931). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 860729). 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 not expected to disrupt MPI protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
3billion RCV001067096 SCV002573371 likely pathogenic MPI-congenital disorder of glycosylation 2022-09-01 criteria provided, single submitter clinical testing The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). While this variant results in missense change, protein truncation variants are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product. The variant has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000860729). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001067096 SCV003929283 pathogenic MPI-congenital disorder of glycosylation 2023-04-26 criteria provided, single submitter clinical testing Variant summary: MPI c.1193T>C (p.Ile398Thr) results in a non-conservative amino acid change located in the Phosphomannose isomerase type I, C-terminal domain (IPR046456) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251494 control chromosomes (gnomAD). c.1193T>C has been reported in the literature in multiple individuals affected with Congenital Disorder Of Glycosylation Type 1B (example: de la Morena-Barrio_2019, Abdel Ghaffar_2020 and Lipinski_2021). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 33643843, 30545931, 33204592).Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Intergen, Intergen Genetics and Rare Diseases Diagnosis Center RCV001067096 SCV003930385 pathogenic MPI-congenital disorder of glycosylation 2023-06-13 criteria provided, single submitter clinical testing
Baylor Genetics RCV001067096 SCV004193277 pathogenic MPI-congenital disorder of glycosylation 2023-09-12 criteria provided, single submitter clinical testing
Natera, Inc. RCV001067096 SCV002089795 likely pathogenic MPI-congenital disorder of glycosylation 2020-09-10 no assertion criteria provided clinical testing

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