Submissions for variant NM_000303.3(PMM2):c.550C>A (p.Pro184Thr)

dbSNP: rs1555449795

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000665976	SCV000790199	uncertain significance	PMM2-congenital disorder of glycosylation	2017-03-15	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000665976	SCV003441819	uncertain significance	PMM2-congenital disorder of glycosylation	2021-09-01	criteria provided, single submitter	clinical testing	This sequence change replaces proline with threonine at codon 184 of the PMM2 protein (p.Pro184Thr). The proline residue is highly conserved and there is a small physicochemical difference between proline and threonine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with PMM2-CDG (PMID: 21541725). ClinVar contains an entry for this variant (Variation ID: 551026). 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: 21541725). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
3billion	RCV000665976	SCV003841266	likely pathogenic	PMM2-congenital disorder of glycosylation	2023-02-23	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 21541725). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.95; 3Cnet: 0.80). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with PMM2 related disorder (PMID: 21541725). 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	RCV004782499	SCV005394974	uncertain significance	not specified	2024-09-11	criteria provided, single submitter	clinical testing	Variant summary: PMM2 c.550C>A (p.Pro184Thr) 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 251486 control chromosomes. c.550C>A has been reported in the literature in individuals affected with Congenital Disorder Of Glycosylation Type 1a who also carried another variant, c.353C>G, in cis (e.g. Vega_2011, Perez-Cerda_2017, Morena-Barrio_2016, Quelhas_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Congenital Disorder Of Glycosylation Type 1a. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 1% of normal phosphomannomutase activity (Vega_2011). The following publications have been ascertained in the context of this evaluation (PMID: 27214821, 28139241, 33340551, 21541725). ClinVar contains an entry for this variant (Variation ID: 551026). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.