rs80338701

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_000303.3(PMM2):c.357C>A(p.Phe119Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000352 in 1,561,744 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: 𝑓 0.000039 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000035 ( 0 hom. )

Consequence

PMM2
NM_000303.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:24O:1

Conservation

PhyloP100: 1.24

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 16 ACMG points.

PM1

In a chain Phosphomannomutase 2 (size 244) in uniprot entity PMM2_HUMAN there are 79 pathogenic changes around while only 2 benign (98%) in NM_000303.3

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.99

PP5

Variant 16-8811088-C-A is Pathogenic according to our data. Variant chr16-8811088-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 7711.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-8811088-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMM2	NM_000303.3 linkuse as main transcript	c.357C>A	p.Phe119Leu	missense_variant	5/8	ENST00000268261.9	NP_000294.1
PMM2	XM_047434215.1 linkuse as main transcript	c.108C>A	p.Phe36Leu	missense_variant	3/6		XP_047290171.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PMM2	ENST00000268261.9 linkuse as main transcript	c.357C>A	p.Phe119Leu	missense_variant	5/8	1	NM_000303.3	ENSP00000268261	P1	O15305-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000436

AC:

AN:

183678

Hom.:

AF XY:

0.0000410

AC XY:

AN XY:

97638

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000108

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000348

AC:

AN:

1409566

Hom.:

Cov.:

AF XY:

0.0000330

AC XY:

AN XY:

697170

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000444

Gnomad4 OTH exome

AF:

0.0000172

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000444

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000773

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:24Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

PMM2-congenital disorder of glycosylation

Pathogenic:15Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 27, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 08, 2014	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 1998	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Feb 07, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Jun 21, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 11, 2019	NM_000303.2(PMM2):c.357C>A(F119L) is classified as pathogenic in the context of congenital disorder of glycosylation type Ia. Sources cited for classification include the following: PMID 24498599, 9781039 and 9140401. Classification of NM_000303.2(PMM2):c.357C>A(F119L) 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Courtagen Diagnostics Laboratory, Courtagen Life Sciences	Jan 14, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Inherited Metabolic Diseases, Karolinska University Hospital	Apr 02, 2020	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 11, 2018	Variant summary: PMM2 c.357C>A (p.Phe119Leu) 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 allele was found at a frequency of 3.2e-05 in 30952 control chromosomes (gnomAD). The variant, c.357C>A, has been reported in the literature in multiple individuals affected with Congenital Disorder of Glycosylation Type 1a (Kjaergaard_1998). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal activity. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 119 of the PMM2 protein (p.Phe119Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with PMM2-CDG (CDG-Ia) (PMID: 9140401, 9781039, 10801058, 11517108, 15645285). ClinVar contains an entry for this variant (Variation ID: 7711). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PMM2 function (PMID: 24498599, 26488408, 27053713). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 16, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 05, 2017	The NM_000303.2(PMM2):c.357C>A missense variant was identified in exon 5 of the PMM2 gene. This substitution creates a minor amino acid change from a phenylalanine to a leucine at position 119, NP_000294.1(PMM2):p.(Phe119Leu). The phenylalanine at this position has moderate conservation (100 vertebrates, UCSC). In silico tools predict this variant to be deleterious (Polyphen, SIFT, Mutation Taster). This variant is not present in the gnomAD population database. It is situated in a PMM domain. It has been previously reported in multiple families with congenital disorder of glycosylation (ClinVar). In addition, functional studies show this variant in compound heterozygous state weakens quartenary structure, destabilises the protein and reduces enzyme activity (Andreotti. et al., (2013) and Noelle et al., (2005)). Based on current information and in association with the NM_000303.2(PMM2):c.470T>C missense variant, this variant has been classified as PATHOGENIC. The presence of these two variants suggests a possible compound heterozygous mode of inheritance which is consistent with congenital disorder of glycosylation. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	As summarized by Matthijs et al. (2000), the PMM2 c.357C>A (p.Phe119Leu) missense variant has been reported across the literature in at least 82 patients with PMM2-associated congenital disorders of glycosylation from 68 families in 11 countries, and is considered a founder variant in Scandinavian populations. The variant was identified in a compound heterozygous state with the common p.Arg141His variant in 68 patients from 56 families; patients compound heterozygous for these variants account for 81%, 50%, 32%, and 30% of the genotypes observed in Denmark, the Netherlands, Sweden, and Germany, respectively. The p.Phe119Leu variant has also been reported in a homozygous state in four patients. The p.Phe119Leu variant is reported at a frequency of 0.00023 in the European (non-Finnish) population of the Exome Aggregation Consortium. In vitro functional studies in E. coli BL21 (DE3) cells demonstrated that the p.Phe119Leu variant results in 25% residual enzyme activity, reduced protein activity and stability, and altered protein quaternary structure as compared to wild type (Kjaergaard et al. 1999; Andreotti et al. 2013). Based on the collective evidence, the p.Phe119Leu variant is classified as pathogenic for congenital disorders of glycosylation, specifically for congenital disorders of glycosylation, type 1a. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not provided

Pathogenic:7

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 07, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Dec 18, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 06, 2022	Functional studies demonstrate a damaging effect with disruption of dimerization and significantly reduced enzyme activity (Andreotti et al., 2013); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 22975760, 26488408, 27053713, 15645285, 30061496, 9781039, 9497260, 12705494, 11409861, 10854097, 15844218, 28373276, 27535533, 9140401, 11517108, 32304219, 32064623, 33643843, 32685345, 33726816, 33413482, 24498599) -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 07, 2014

- -

PMM2-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 24, 2024

The PMM2 c.357C>A variant is predicted to result in the amino acid substitution p.Phe119Leu. This variant, when present in the compound heterozygous or homozygous states, has been repeatedly reported to be causative for congenital disorder of glycosylation type Ia (CDG) (Matthijs et al. 1997. PubMed ID: 9140401; Kjaergaard et al. 2001. PubMed ID: 11517108; Andreotti et al. 2013. PubMed ID: 24498599). This variant is reported in 0.010% of alleles in individuals of European (Non-Finnish) descent in gnomAD and interpreted as pathogenic in ClinVar by multiple independent submitters (https://www.ncbi.nlm.nih.gov/clinvar/variation/7711). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

D;D

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Pathogenic

0.34

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.1

.;H

MutationTaster

Benign

1.0

A;A;A;A;A

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-5.8

D;D

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0010

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

.;D

Vest4

0.93

MutPred

0.97

.;Loss of methylation at K115 (P = 0.0891);

MVP

0.98

MPC

0.025

ClinPred

0.99

GERP RS

5.4

Varity_R

0.97

gMVP

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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