rs141498002

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong

The NM_000303.3(PMM2):c.368G>A(p.Arg123Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000268 in 1,571,002 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00028 ( 0 hom. )

Consequence

PMM2
NM_000303.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16

Conservation

PhyloP100: 9.79

Variant links:

Genes affected

PMM2 (HGNC:9115): (phosphomannomutase 2) The protein encoded by this gene catalyzes the isomerization of mannose 6-phosphate to mannose 1-phosphate, which is a precursor to GDP-mannose necessary for the synthesis of dolichol-P-oligosaccharides. Mutations in this gene have been shown to cause defects in glycoprotein biosynthesis, which manifests as carbohydrate-deficient glycoprotein syndrome type I. [provided by RefSeq, Jul 2008]

PMM2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a binding_site (size 0) in uniprot entity PMM2_HUMAN

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.918

PP5

Variant 16-8811099-G-A is Pathogenic according to our data. Variant chr16-8811099-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 265255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-8811099-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMM2	NM_000303.3 link	c.368G>A	p.Arg123Gln	missense_variant	Exon 5 of 8	ENST00000268261.9	NP_000294.1	O15305-1A0A0S2Z4J6Q59F02
PMM2	XM_047434215.1 link	c.119G>A	p.Arg40Gln	missense_variant	Exon 3 of 6		XP_047290171.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMM2	ENST00000268261.9 link	c.368G>A	p.Arg123Gln	missense_variant	Exon 5 of 8	1	NM_000303.3	ENSP00000268261.4		O15305-1

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000114

AC:

AN:

192596

Hom.:

AF XY:

0.000127

AC XY:

AN XY:

102744

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000134

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000133

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000568

Gnomad NFE exome

AF:

0.000191

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000279

AC:

396

AN:

1418822

Hom.:

Cov.:

AF XY:

0.000271

AC XY:

190

AN XY:

702024

show subpopulations

Gnomad4 AFR exome

AF:

0.0000616

Gnomad4 AMR exome

AF:

0.000223

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000132

Gnomad4 SAS exome

AF:

0.0000123

Gnomad4 FIN exome

AF:

0.000198

Gnomad4 NFE exome

AF:

0.000332

Gnomad4 OTH exome

AF:

0.000137

GnomAD4 genome

AF:

0.000164

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00143

Alfa

AF:

0.000113

Hom.:

Bravo

AF:

0.000212

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ExAC

AF:

0.0000850

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

PMM2-congenital disorder of glycosylation

Pathogenic:11

Dec 24, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000303.2(PMM2):c.368G>A(R123Q) is classified as pathogenic in the context of congenital disorder of glycosylation type Ia. Sources cited for classification include the following: PMID 15844218, 11156536, 21541725, 11409861, 25497157, 17166182, 25355454 and 11715002. Classification of NM_000303.2(PMM2):c.368G>A(R123Q) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

Aug 29, 2018

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

ACMG codes: PS3, PM2, PP3, PP5 -

Sep 10, 2020

Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 123 of the PMM2 protein (p.Arg123Gln). This variant is present in population databases (rs141498002, gnomAD 0.02%). This missense change has been observed in individual(s) with PMM2-CDG (PMID: 9497260, 15844218, 21541725, 22012410). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 265255). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PMM2 protein function. Experimental studies have shown that this missense change affects PMM2 function (PMID: 21541725, 26014514). For these reasons, this variant has been classified as Pathogenic. -

Oct 09, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with congenital disorder of glycosylation type Ia (MIM# 212065). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 – This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (30 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position to leucine has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the Phosphomannomutase annotated domain (NCBI). (I) 0801 – This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has been previously reported as pathogenic in patients with congenital disorder of glycosylation type Ia (ClinVar, PMID: 9497260, 15844218, 22012410). (SP) 1102 - Strong phenotype match for this individual. (SP) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Mar 13, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 30, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 04, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Jul 28, 2017

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:3

Nov 16, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate that R123Q affects protein stability, causes a 40% reduction of the protein half-life and results in no residual enzyme activity (PMID: 26014514, 21541725); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21541725, 28807751, 30304743, 28671287, 34930662, 22012410, 11156536, 11715002, 10527672, 31115488, 28915903, 25497157, 25355454, 17166182, 15844218, 11409861, 28122681, 10922383, 20652024, 12705494, 32071842, 9497260, 26014514) -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 08, 2019

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PS4_Moderate, PM2, PP3, PP4 -

Inborn genetic diseases

Pathogenic:1

Jan 28, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.368G>A (p.R123Q) alteration is located in exon 5 (coding exon 5) of the PMM2 gene. This alteration results from a G to A substitution at nucleotide position 368, causing the arginine (R) at amino acid position 123 to be replaced by a glutamine (Q). Based on data from gnomAD, the A allele has an overall frequency of 0.01% (30/223998) total alleles studied. The highest observed frequency was 0.02% (18/94022) of European (non-Finnish) alleles. This mutation has been reported in conjunction with multiple PMM2 missense alterations in individuals with PMM2-related congenital disorder of glycosylation (Matthijs, 1998; Westphal, 2001; Le Bizec, 2005; Vega, 2011)._x000D_ _x000D_ Reference:_x000D_ _x000D_ Westphal V, et al. Genet Med. Nov-Dec 2001;3(6):393-8. This amino acid position is highly conserved in available vertebrate species. Analysis of this variant in both E. coli and S. cerevisiae demonstrated reduced or absent residual activity when compared to wildtype (Westphal, 2001; Vega, 2011; Yuste-Checa, 2015). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

PMM2-related disorder

Pathogenic:1

Mar 31, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PMM2 c.368G>A variant is predicted to result in the amino acid substitution p.Arg123Gln. This variant was reported in multiple individuals with congenital disorder of glycosylation 1a (see, for example, Matthijs et al. 1998. PubMed ID: 9497260; Vega et al. 2011. PubMed ID: 21541725; Casado et al. 2012. PubMed ID: 22012410; Vicario et al. 2017. PubMed ID: 28807751). In vitro function analysis indicates that this nucleotide change abolishes PMM2 enzyme activity (Vega et al. 2011. PubMed ID: 21541725; Yuste-Checa et al. 2015. PubMed ID: 26014514). This variant is reported in 0.019% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.94

D;D

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.95

D;D

M_CAP

Pathogenic

0.34

MetaRNN

Pathogenic

0.92

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.1

.;H

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-3.8

D;D

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.045

D;D

Polyphen

1.0

.;D

Vest4

1.0

MVP

0.98

MPC

0.041

ClinPred

0.97

GERP RS

5.4

Varity_R

0.93

gMVP

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over