rs80338703

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong

The NM_000303.3(PMM2):c.415G>A(p.Glu139Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000014 in 1,423,654 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 Pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PMM2
NM_000303.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9O:1

Conservation

PhyloP100: 5.49

Publications

32 publications found

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 Gene-Disease associations (from GenCC):

congenital disorder of glycosylation type I
Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
PMM2-congenital disorder of glycosylation
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia, ClinGen

PMM2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 17 ACMG points.

PM1

In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_000303.3

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 89 curated pathogenic missense variants (we use a threshold of 10). The gene has 24 curated benign missense variants. Gene score misZ: -1.3872 (below the threshold of 3.09). Trascript score misZ: -1.8083 (below the threshold of 3.09). GenCC associations: The gene is linked to PMM2-congenital disorder of glycosylation, congenital disorder of glycosylation type I.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.946

PP5

Variant 16-8811146-G-A is Pathogenic according to our data. Variant chr16-8811146-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 21143.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMM2	NM_000303.3 link	c.415G>A	p.Glu139Lys	missense_variant	Exon 5 of 8	ENST00000268261.9	NP_000294.1
PMM2	XM_047434215.1 link	c.166G>A	p.Glu56Lys	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.415G>A	p.Glu139Lys	missense_variant	Exon 5 of 8	1	NM_000303.3	ENSP00000268261.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000140

AC:

AN:

1423654

Hom.:

Cov.:

AF XY:

0.00000142

AC XY:

AN XY:

704786

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32636

American (AMR)

AF:

0.00

AC:

AN:

41186

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25488

East Asian (EAS)

AF:

0.0000261

AC:

AN:

38306

South Asian (SAS)

AF:

0.00

AC:

AN:

82098

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50690

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5726

European-Non Finnish (NFE)

AF:

9.18e-7

AC:

AN:

1088758

Other (OTH)

AF:

0.00

AC:

AN:

58766

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000248

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

PMM2-congenital disorder of glycosylation

Pathogenic:6Other:1

Mar 09, 2021

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Sep 08, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method: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. For these reasons, this variant has been classified as Pathogenic. Studies have shown that this missense change is associated with altered splicing resulting in multiple RNA products (PMID: 10571956). Experimental studies have shown that this missense change affects PMM2 function (PMID: 10571956). ClinVar contains an entry for this variant (Variation ID: 21143). This missense change has been observed in individual(s) with congenital disorder of glycosylation type 1a (PMID: 10571956). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 139 of the PMM2 protein (p.Glu139Lys).

Oct 02, 2021

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (VCV000021143.5, PMID: 15844218, 19357119, PM3_S). It is not observed in the gnomAD v2.1.1 dataset (PM2). Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 15844218). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.701, 3Cnet: 0.940, PP3). Patient's phenotype is considered compatible with Congenital disorder of glycosylation, type Ia (3billion dataset, PP4). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

May 25, 2017

Counsyl

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Nov 30, 2018

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: PMM2 c.415G>A (p.Glu139Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. At least one publication reports experimental evidence that this variant affects mRNA splicing, resulting in exon 5 skipping (Vuillaumier-Barrot_1999). The variant was absent in 189894 control chromosomes (gnomAD). The variant, c.415G>A, has been reported in the literature in multiple individuals affected with Congenital Disorder of Glycosylation Type 1a and was reported to be a founder mutation in the French population (Vuillaumier-Barrot_1999, LeBizec_2005). These data indicate that the variant is very likely to be associated with disease. Two publications from the same group report experimental evidence evaluating an impact on protein function (Vuillaumier-Barrot_1999, LeBizec_2005). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

Feb 18, 2019

Dobyns Lab, Seattle Children's Research Institute

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

not provided

Pathogenic:2

Feb 07, 2017

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The E139K variant in the PMM2 gene has been reported previously numerous times in association with CDG type 1a (Vullamier-Barrot et al., 1999; Le Bizec et al., 2005; Romano et al., 2009). Functional studies demonstrate that this variant disrupts a splicing enhancer sequence, which causes skipping of exon 5 and ultimately results in decreased protein activity (Vullamier-Barrot et al., 1999; Le Bizec et al., 2005; Smith et al., 2006). The E139K variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant is a non-conservative amino acid substitution, which occurs at a position that is conserved across species. Missense variants in nearby residues (R141C, R141H, F144L) have been reported in the Human Gene Mutation Database in association with CDG type 1a (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret E139K as a pathogenic variant.

May 09, 2014

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Congenital cerebellar hypoplasia

Pathogenic:1

University of Washington Center for Mendelian Genomics, University of Washington

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.44

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.77

D;D

Eigen

Benign

0.015

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.95

D;D

MetaSVM

Pathogenic

0.91

MutationAssessor

Benign

0.0

.;M

PhyloP100

5.5

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-2.1

N;N

REVEL

Benign

0.0

Sift

Benign

0.11

T;T

Sift4G

Benign

0.24

T;T

Vest4

0.92

ClinPred

0.89

GERP RS

5.4

Varity_R

0.79

gMVP

0.82

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over