Submissions for variant NM_000303.3(PMM2):c.368G>A (p.Arg123Gln) (rs141498002)

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Total submissions: 8

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000576764	SCV000678047	pathogenic	Carbohydrate-deficient glycoprotein syndrome type I	2017-06-12	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen	RCV000576764	SCV000733549	pathogenic	Carbohydrate-deficient glycoprotein syndrome type I		no assertion criteria provided	clinical testing
GeneDx	RCV000254854	SCV000321928	pathogenic	not provided	2017-12-20	criteria provided, single submitter	clinical testing	The R123Q pathogenic variant in the PMM2 gene has been reported previously in many patients with congenital disorder of glycosylation, type 1a, more recently known as PMM2-CDG (Le Bizec et al., 2005; Matthijs et al., 1999; Vega et al., 2011). The R123Q variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a substrate binding site that is conserved across species. Functional analyses have demonstrated that R123Q affects protein stability, causes a 40% reduction of the protein half-life and results in no residual enzyme activity (Vega et al, 2011; Yuste-Checa et al., 2015). Another missense variant in the same codon (R123G) and others in nearby residues (T118S, F119L, I120T) have been reported in the Human Gene Mutation Database in association with PMM2-CDG (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, we interpret R123Q as a pathogenic variant.
Genome Diagnostics Laboratory,University Medical Center Utrecht	RCV000576764	SCV000743894	pathogenic	Carbohydrate-deficient glycoprotein syndrome type I	2017-07-28	criteria provided, single submitter	clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000576764	SCV000993427	likely pathogenic	Carbohydrate-deficient glycoprotein syndrome type I	2018-08-29	criteria provided, single submitter	research
Integrated Genetics/Laboratory Corporation of America	RCV000576764	SCV000696495	pathogenic	Carbohydrate-deficient glycoprotein syndrome type I	2016-08-04	criteria provided, single submitter	clinical testing	Variant summary: The PMM2 c.368G>A (p.Arg123Gln) variant involves the alteration of a conserved nucleotide. 4/5 in silico tools predict a deleterious outcome. This variant was found in 3/28750 control chromosomes at a frequency of 0.0001043, which does not exceed the estimated maximal expected allele frequency of a pathogenic PMM2 variant (0.0055902). This variant has been reported in many CDG patients as compound heterozygotes with another pathogenic variant in trans. Functional studies showed that variant of interest led to null activity of the protein and classified the variant as one of the severe mutations. Taken together, this variant is classified as pathogenic.
Invitae	RCV000576764	SCV000950705	pathogenic	Carbohydrate-deficient glycoprotein syndrome type I	2018-10-16	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with glutamine at codon 123 of the PMM2 protein (p.Arg123Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs141498002, ExAC 0.07%). This variant has been observed in many individuals affected with PMM2-CDG (PMID: 9497260, 21541725, 22012410,15844218). ClinVar contains an entry for this variant (Variation ID: 265255). Experimental studies have shown that this missense change reduces PMM2 enzyme activity and reduces protein stability (PMID: 21541725, 26014514). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic	RCV000576764	SCV000782487	uncertain significance	Carbohydrate-deficient glycoprotein syndrome type I	2016-09-22	criteria provided, single submitter	clinical testing

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