rs80338707

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_000303.3(PMM2):c.691G>A(p.Val231Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000564 in 1,613,918 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V231L) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000057 ( 0 hom. )

Consequence

PMM2
NM_000303.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:20O:1

Conservation

PhyloP100: 8.29

Publications

54 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:

ENSG00000260350 (HGNC:58482):

ENSG00000260350 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 19 ACMG points.

PM1

In a hotspot region, there are 16 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 13 uncertain in NM_000303.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-8847775-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3008048.Status of the report is criteria_provided_single_submitter, 1 stars.

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, 0.958

PP5

Variant 16-8847775-G-A is Pathogenic according to our data. Variant chr16-8847775-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 7719.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.691G>A	p.Val231Met	missense_variant	Exon 8 of 8	ENST00000268261.9	NP_000294.1
PMM2	XM_047434215.1 link	c.442G>A	p.Val148Met	missense_variant	Exon 6 of 6		XP_047290171.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMM2	ENST00000268261.9 link	c.691G>A	p.Val231Met	missense_variant	Exon 8 of 8	1	NM_000303.3	ENSP00000268261.4

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000677

AC:

AN:

251246

AF XY:

0.0000663

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000968

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000575

AC:

AN:

1461720

Hom.:

Cov.:

AF XY:

0.0000536

AC XY:

AN XY:

727164

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000447

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.000104

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53334

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000603

AC:

AN:

1111930

Other (OTH)

AF:

0.0000662

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41458

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000105

Hom.:

Bravo

AF:

0.0000416

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000576

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:20Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

PMM2-congenital disorder of glycosylation

Pathogenic:14Other:1

Jan 12, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 18, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jun 10, 2020

Research Laboratories, P. D. Hinduja Hospital & MRC

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

The p.Val231Met variant has been classified as pathogenic based on several reports in ClinVar and the literature reports.

Dec 20, 2019

Myriad Genetics, Inc.

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NM_000303.2(PMM2):c.691G>A(V231M) is classified as pathogenic in the context of congenital disorder of glycosylation type Ia. Sources cited for classification include the following: PMID 11156536, 15844218 and 10386614. Classification of NM_000303.2(PMM2):c.691G>A(V231M) 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.

Sep 22, 2022

Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Pediatric Metabolic Diseases, Hacettepe University

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 16, 2020

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

Oct 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 231 of the PMM2 protein (p.Val231Met). This variant is present in population databases (rs80338707, gnomAD 0.01%). This missense change has been observed in individual(s) with PMM2-CDG, being one of the most common causes of the disease in European populations (PMID: 9497260, 10801058, 15844218, 23430838, 25355454). 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: 7719). 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) indicates that this missense variant is expected to disrupt PMM2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PMM2 function (PMID: 10386614). For these reasons, this variant has been classified as Pathogenic.

Apr 02, 2020

Centre for Inherited Metabolic Diseases, Karolinska University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Oct 19, 2020

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_v1.3.2, 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 PMM2-congenital disorder of glycosylation (PMM2-CDG). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to methionine (exon 8). (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD v2 <0.01 for a recessive condition (22 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position 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 annotated PMM domain (NCBI, Decipher, PDB). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been previously reported as pathogenic in patients with PMM2-CDG (ClinVar, LOVD, PMID: 28425223, 30397276). (SP) 1102 - Strong phenotype match for this individual. (SP) 1206 - This variant has been shown to be paternally inherited (VCGS #20G001738). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Apr 11, 2023

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM3_Very Strong, PS3, PM1, PM2, PP3

Nov 15, 2018

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

The homozygous p.Val231Met variant in PMM2 was identified by our study in two siblings with Congenital Disorder of Glycosylation. The p.Val231Met variant is pathogenic based off of multiple reports in ClinVar and the literature.

Aug 01, 2000

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Aug 21, 2017

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.691G>A (p.Val231Met) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 7/120856 control chromosomes at a frequency of 0.0000579, which does not exceed the estimated maximal expected allele frequency of a pathogenic PMM2 variant (0.0055902). This variant has been reported in many pts/families with evidence of co-segregation of the variant with disease. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

not provided

Pathogenic:6

Dec 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jun 16, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate that the V231M variant results in decreased enzymatic activity and thermal stability (Pirard et al., 1999); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9497260, 23430838, 25355454, 31981409, 18203160, 22975760, 19168813, 9140401, 15714316, 10386614, 10801058, 10922383, 28425223, 15844218, 11409861, 31589614, 33643843, 33133147, 33413482, 31319225, 33726816, Vignogna2022[preprint], 34420056)

Jun 12, 2017

Eurofins Ntd Llc (ga)

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

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

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.93

D;D;.

Eigen

Pathogenic

0.74

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Pathogenic

0.54

MetaRNN

Pathogenic

0.96

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

0.0

.;H;.

PhyloP100

8.3

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-2.9

D;D;D

REVEL

Benign

0.0

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0010

D;D;D

Vest4

0.82

ClinPred

0.84

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.92

gMVP

0.91

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over