ClinVar Miner

Submissions for variant NM_000303.3(PMM2):c.647A>T (p.Asn216Ile)

dbSNP: rs78290141
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000724043 SCV000232514 pathogenic not provided 2014-07-17 criteria provided, single submitter clinical testing
Invitae RCV000008146 SCV000836724 pathogenic PMM2-congenital disorder of glycosylation 2023-06-22 criteria provided, single submitter clinical testing 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. Experimental studies have shown that this missense change affects PMM2 function (PMID: 9140401, 25355454). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 7707). This missense change has been observed in individuals with PMM2-congenital disorder of glycosylation (PMID: 9140401, 9497260, 11875054, 12905014, 23430838, 25355454). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 216 of the PMM2 protein (p.Asn216Ile).
Pediatric Metabolic Diseases, Hacettepe University RCV000008146 SCV000998569 likely pathogenic PMM2-congenital disorder of glycosylation criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000008146 SCV002500420 pathogenic PMM2-congenital disorder of glycosylation 2022-03-02 criteria provided, single submitter clinical testing Variant summary: PMM2 c.647A>T (p.Asn216Ile) 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 was absent in 251180 control chromosomes. c.647A>T has been reported in the literature in individuals affected with Congenital Disorder Of Glycosylation Type 1a. These data indicate that the variant may be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
3billion RCV000008146 SCV002572753 pathogenic PMM2-congenital disorder of glycosylation 2022-09-01 criteria provided, single submitter clinical testing The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.93; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000007707). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 12905014). A different missense change at the same codon (p.Asn216Ser) has been reported to be associated with PMM2 -related disorder (PMID: 11058896). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens RCV000008146 SCV002577412 pathogenic PMM2-congenital disorder of glycosylation 2022-06-28 criteria provided, single submitter clinical testing PS4, PM1, PM2, PM5, PP2, PP3, PP5
Baylor Genetics RCV000008146 SCV004205277 pathogenic PMM2-congenital disorder of glycosylation 2023-06-17 criteria provided, single submitter clinical testing
OMIM RCV000008146 SCV000028351 pathogenic PMM2-congenital disorder of glycosylation 2003-10-01 no assertion criteria provided literature only
Natera, Inc. RCV000008146 SCV002092446 pathogenic PMM2-congenital disorder of glycosylation 2021-07-07 no assertion criteria provided clinical testing

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