ClinVar Miner

Submissions for variant NM_002435.3(MPI):c.656G>A (p.Arg219Gln) (rs104894489)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000015419 SCV000486500 likely pathogenic Congenital disorder of glycosylation type 1B 2016-07-14 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000015419 SCV000893378 likely pathogenic Congenital disorder of glycosylation type 1B 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000015419 SCV000393945 pathogenic Congenital disorder of glycosylation type 1B 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.
Invitae RCV000015419 SCV000962921 pathogenic Congenital disorder of glycosylation type 1B 2019-01-07 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 219 of the MPI protein (p.Arg219Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs104894489, ExAC 0.08%). This variant has been observed in individuals with CDG type Ib (PMID: 10980531, 18928705), and has been shown to segregate with disease in a family (PMID: 11350186). ClinVar contains an entry for this variant (Variation ID: 14345). This variant has been reported to affect MPI protein function (PMID: 9525984, 24421398). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000015419 SCV000035682 pathogenic Congenital disorder of glycosylation type 1B 2000-09-01 no assertion criteria provided literature only

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