ClinVar Miner

Submissions for variant NM_002435.3(MPI):c.656G>A (p.Arg219Gln)

gnomAD frequency: 0.00021  dbSNP: rs104894489
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000015419 SCV000393945 pathogenic MPI-congenital disorder of glycosylation 2017-04-27 criteria provided, single submitter clinical testing The MPI c.656G>A (p.Arg219Gln) missense variant has been reported in five studies in which it is found in a total of six individuals with MPI- congenital disorders of glycosylation (CDG-Ib), including one homozygote and five compound heterozygotes (Niehues et al. 1998; Schollen et al. 2000; Westphal et al. 2001; Martín Hernández et al. 2008; Helander et al. 2014). The variant was also identified in a homozygous state in an individual who showed elevated carbohydrate-deficient transferrin levels but no other clinical signs of MPI-CDG (CDG-Ib), and in a heterozygous state in three unaffected parents of patients. The variant was absent from 50 controls but is reported at a frequency of 0.00078 in the European (non-Finnish) population of the Exome Aggregation Consortium. Expression studies in COS-7 cells showed that the variant protein resulted in MPI activity indistinguishable from background, while expression of normal MPI increased specific activity approximately 10 fold when compared with controls (Niehues et al. 1998). Based on the collective evidence, the p.Arg219Gln variant is classified as pathogenic for congenital disorders of glycosylation. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Fulgent Genetics, Fulgent Genetics RCV000015419 SCV000893378 pathogenic MPI-congenital disorder of glycosylation 2022-02-15 criteria provided, single submitter clinical testing
Invitae RCV000015419 SCV000962921 pathogenic MPI-congenital disorder of glycosylation 2024-01-22 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 219 of the MPI protein (p.Arg219Gln). This variant is present in population databases (rs104894489, gnomAD 0.05%). This missense change has been observed in individual(s) with CDG type Ib (PMID: 10980531, 11350186, 18928705). 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: 14345). 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%. Experimental studies have shown that this missense change affects MPI function (PMID: 9525984, 24421398). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000015419 SCV001524348 pathogenic MPI-congenital disorder of glycosylation 2020-09-18 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Genetic Services Laboratory, University of Chicago RCV001818161 SCV002069686 pathogenic not provided 2021-08-09 criteria provided, single submitter clinical testing DNA sequence analysis of the MPI gene demonstrated two sequence changes. The first sequence change, c.656G>A, in exon 5, results in an amino acid change, p.Arg219Gln. This sequence change has been described in gnomAD with a low population frequency of 0.029% (dbSNP rs104894489). The p.Arg219Gln change affects a highly conserved amino acid residue located in a domain of the MPI protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg219Gln substitution. This sequence change has been reported in the homozygous and compound heterozygous states in multiple individuals with features of congenital disorder of glycosylation (PMIDs: 10980531, 18928705, 11350186, 9525984). Functional studies have also demonstrated that the p.Arg219Gln change affects MPI protein function (PMID: 9525984, 24421398). Based on the collective evidence, the p.Arg219Gln variant is classified as pathogenic for congenital disorders of glycosylation
GeneDx RCV001818161 SCV002504183 pathogenic not provided 2022-04-21 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect, specifically, R219Q is associated with significantly reduced mannose-6-phosphate isomerase activity compared to wild-type (Niehues et al., 1998); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 24508628, 10980531, 26206375, 9525984, 18928705, 28928705, 24421398, 30545931, 11350186, 33204592, 31589614, 33643843, 33413482)
OMIM RCV000015419 SCV000035682 pathogenic MPI-congenital disorder of glycosylation 2000-09-01 no assertion criteria provided literature only
Counsyl RCV000015419 SCV000486500 likely pathogenic MPI-congenital disorder of glycosylation 2016-07-14 no assertion criteria provided clinical testing

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