rs190521996

Positions:

chr16-8811660-T-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The ENST00000268261.9(PMM2):c.470T>C(p.Phe157Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000573 in 1,612,830 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F157C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00040 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00059 ( 0 hom. )

Consequence

PMM2
ENST00000268261.9 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:21

Conservation

PhyloP100: 7.78

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 18 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in ENST00000268261.9

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-8811660-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1993071.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.944

PP5

Variant 16-8811660-T-C is Pathogenic according to our data. Variant chr16-8811660-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-8811660-T-C is described in Lovd as [Pathogenic]. Variant chr16-8811660-T-C 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.470T>C	p.Phe157Ser	missense_variant	6/8	ENST00000268261.9	NP_000294.1
PMM2	XM_047434215.1 linkuse as main transcript	c.221T>C	p.Phe74Ser	missense_variant	4/6		XP_047290171.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PMM2	ENST00000268261.9 linkuse as main transcript	c.470T>C	p.Phe157Ser	missense_variant	6/8	1	NM_000303.3	ENSP00000268261	P1	O15305-1

Frequencies

GnomAD3 genomes

AF:

0.000401

AC:

AN:

152250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

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:

0.000617

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.000294

AC:

AN:

251382

Hom.:

AF XY:

0.000258

AC XY:

AN XY:

135864

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000289

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:

0.000537

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000591

AC:

863

AN:

1460462

Hom.:

Cov.:

AF XY:

0.000594

AC XY:

432

AN XY:

726670

show subpopulations

Gnomad4 AFR exome

AF:

0.0000897

Gnomad4 AMR exome

AF:

0.000268

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000745

Gnomad4 OTH exome

AF:

0.000282

GnomAD4 genome

AF:

0.000400

AC:

AN:

152368

Hom.:

Cov.:

AF XY:

0.000416

AC XY:

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.000216

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000617

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.000462

Hom.:

Bravo

AF:

0.000370

ESP6500AA

AF:

0.000455

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000272

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000533

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:21

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

PMM2-congenital disorder of glycosylation

Pathogenic:11

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 27, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 03, 2016	Variant summary: The PMM2 c.470T>C (p.Phe157Ser) variant causes a missense mutation involving a conserved nucleotide with 5/5 in silico tools predicting a damaging outcome, which functional studies support this prediction. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 33/121274 (1/3675), which does not exceed the estimated maximal expected allele frequency for a pathogenic PMM2 variant of 1/178. (0.0055902). The variant of interest has been reported in multiple affected individuals via publications, along with a reputable clinical laboratory citing the variant as "likely pathogenic." Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jun 24, 2022	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) 0115 - Variants in this gene are known to have variable expressivity. The clinical manifestations and course are highly variable, ranging from infants who die in the first year of life to mildly affected adults. (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from phenylalanine to serine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 91 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in at least twenty individuals with congenital disorder of glycosylation, including compound heterozygotes (PMID: 33340551). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, no assertion criteria provided	clinical testing	Genetics laboratory, Department of Obstetrics & Gynae, Institute of Kidney Diseases & Research Centre Dr. H.L. Trivedi Institute Of Transplantation Sciences	Jun 07, 2024	A heterozygous missense variant c.470T>C in PMM2 gene (chr16:8905517; Depth: 200x) was detected. This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 157 of the PMM2 protein (p.Phe157Ser). This variant is present in population databases (rs190521996, gnomAD 0.06%). This missense change has been observed in individual(s) with congenital disorder of glycosylation type Ia. In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. 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, 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. For these reasons, this variant has been classified as pathogenic according to the ACMG guidelines. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	Across a selection of the available literature, the PMM2 c.470T>C (p.Phe157Ser) missense variant is reported in a compound heterozygous state with a second variant in eight patients with congenital disorder of glycosylation type 1a (CDG1a), and in one patient where zygosity information is not provided (Matthijs et al. 1999; Briones et al. 2002; Noelle et al. 2005; Romano et al. 2009; Vega et al. 2011; Casado et al. 2012; Resende et al. 2014). Nearly all of these patients exhibited a severe phenotype and residual PMM2 enzyme activity in patient fibroblasts was extremely low or undetectable. Control data are unavailable for this variant, which is reported at a frequency of 0.00081 in the European American population of the Exome Sequencing Project. Analysis of the p.Phe157Ser variant in a prokaryotic expression system showed that the variant affected the stability and structure, and significantly decreased the half-life of the protein (Vega et al. 2011). Based on the collective evidence, the p.Phe157Ser variant is classified as pathogenic for congenital disorders of glycosylation. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 20, 2019	NM_000303.2(PMM2):c.470T>C(F157S) is classified as pathogenic in the context of congenital disorder of glycosylation type Ia. Sources cited for classification include the following: PMID 11156536, 17166182, 12607543, 12705494, 19396570, 17920054, 21541725 and 15645285. Classification of NM_000303.2(PMM2):c.470T>C(F157S) 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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 157 of the PMM2 protein (p.Phe157Ser). This variant is present in population databases (rs190521996, gnomAD 0.06%). This missense change has been observed in individual(s) with congenital disorder of glycosylation type Ia (PMID: 11156536, 15645285, 19357119, 21541725, 22012410, 24739649, 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: 188763). 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 95%. Experimental studies have shown that this missense change affects PMM2 function (PMID: 21541725). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Dec 06, 2022	PS3, PM3_Strong, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 11, 2022	- -

not provided

Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2023	Published functional studies demonstrate this variant results in complete loss of enzyme activity and may impact the stability and/or structure of the protein (Romano et al., 2009; Vega et al., 2011); 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: 17166182, 15844218, 15645285, 29482223, 11343337, 18948042, 19396570, 22012410, 19357119, 10527672, 11156536, 24739649, 28373276, 17920054, 12705494, 12607543, 23430838, 17158594, 25497157, 25355454, 21541725, 32304219, 32630370, 32841164, 33643843, 33413482, 31589614, 34598035, 33580824, 35279850, 33340551) -
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	Mayo Clinic Laboratories, Mayo Clinic	May 13, 2021	PS3, PS4, PM2, PM3_strong, PP3, PP4 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 15, 2021	DNA sequence analysis of the PMM2 gene demonstrated a sequence change, c.470T>C, in exon 6 that results in an amino acid change, p.Phe157Ser. This sequence change has been described in the gnomAD database with a frequency of 0.06% in the non-Finnish European subpopulation (dbSNP rs190521996). This sequence change has been described in the compound heterozygous state with other pathogenic/likely pathogenic variants in individuals with PMM2-related disorder (PMIDs: 24739649, 15645285, 11156536, 19357119, 25355454, 22012410). The p.Phe157Ser change affects a highly conserved amino acid residue located in the cap domain of the PMM2 protein. The p.Phe157Ser substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Functional studies suggest p.Phe157Ser disrupts the stability and activity of the PMM2 protein (PMID: 21541725). Collectively, this evidence suggests p.Phe157Ser is likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	PMM2: PM3:Very Strong, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Sep 15, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

PMM2-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 11, 2024

The PMM2 c.470T>C variant is predicted to result in the amino acid substitution p.Phe157Ser. This variant has been documented in many unrelated individuals to be causative for autosomal recessive congenital disorders of glycosylation type Ia due to abolished phosphomannomutase 2 enzyme activity (Matthijs et al. 1999. PubMed ID: 10527672; Vega et al. 2011. PubMed ID: 21541725; Resende et al. 2014. PubMed ID: 24739649). It has been interpreted as pathogenic or likely pathogenic by many independent submitters to ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/188763/). This variant is reported in 0.060% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Taken together, this variant is interpreted as pathogenic. -

See cases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Jan 29, 2021

ACMG classification criteria: PS3, PS4, PM3 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.92

D;D;.

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Pathogenic

0.61

MetaRNN

Pathogenic

0.94

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.7

.;H;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-6.1

D;D;D

REVEL

Pathogenic

0.98

Sift

Uncertain

0.0010

D;D;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

.;D;.

Vest4

0.98

MVP

0.98

MPC

0.041

ClinPred

0.95

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.99

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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