rs80338708

Positions:

Variant summary

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

The NM_000303.3(PMM2):c.710C>G(p.Thr237Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00017 in 1,613,588 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. T237K) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

PMM2
NM_000303.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:22

Conservation

PhyloP100: 6.55

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a helix (size 11) in uniprot entity PMM2_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) 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 chr16-8847794-C-A is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.985

PP5

Variant 16-8847794-C-G is Pathogenic according to our data. Variant chr16-8847794-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 7716.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-8847794-C-G is described in Lovd as [Likely_pathogenic]. Variant chr16-8847794-C-G 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.710C>G	p.Thr237Arg	missense_variant	8/8	ENST00000268261.9	NP_000294.1
PMM2	XM_047434215.1 linkuse as main transcript	c.461C>G	p.Thr154Arg	missense_variant	6/6		XP_047290171.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PMM2	ENST00000268261.9 linkuse as main transcript	c.710C>G	p.Thr237Arg	missense_variant	8/8	1	NM_000303.3	ENSP00000268261	P1	O15305-1
	ENST00000567942.1 linkuse as main transcript	n.286G>C		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes

AF:

0.000217

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.000470

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000127

AC:

AN:

251084

Hom.:

AF XY:

0.000140

AC XY:

AN XY:

135728

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:

0.000273

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000165

AC:

241

AN:

1461276

Hom.:

Cov.:

AF XY:

0.000155

AC XY:

113

AN XY:

726976

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.000211

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.000217

AC:

AN:

152312

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000470

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000123

Hom.:

Bravo

AF:

0.000174

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000148

AC:

EpiCase

AF:

0.000545

EpiControl

AF:

0.000356

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:22

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

PMM2-congenital disorder of glycosylation

Pathogenic:14

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 24, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1999	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 27, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Jun 28, 2022	PS4, PM1, PM2, PM5, PP2, PP3, PP5 -
Likely pathogenic, criteria provided, single submitter	research	Molecular Biology Laboratory, Fundació Puigvert	Feb 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PP3,PP5. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 23, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 237 of the PMM2 protein (p.Thr237Arg). This variant is present in population databases (rs80338708, gnomAD 0.03%). This missense change has been observed in individuals with PMM2-CDG (PMID: 9497260, 10602363, 15714316, 25355454, 25497157). ClinVar contains an entry for this variant (Variation ID: 7716). 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: 10602363). This variant disrupts the p.Thr237 amino acid residue in PMM2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9497260, 11156536, 11589167, 11891694, 15714316). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The PMM2 c.710C>G (p.Thr237Arg) missense variant has been reported in at least six studies in which it is found in a total of nine patients with congenital disorders of glycosylation type 1a, all of whom were in a compound heterozygous state with either one or two other missense variants (Matthijs et al. 1998; Kjaergaard et al. 1999; GrÃ¼newald et al. 2001; Aronica et al. 2005; Le Bizec et al. 2005; GarcÃa-LÃ³pez et al. 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.00027 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies in E.coli showed that the variant protein was produced in similar quantities compared to wild type and was present in the same subcellular fraction but had no detectable catalytic activity (Kjaergaard et al. 1999). Based on the collective evidence, the p.Thr237Arg variant is classified as pathogenic for congenital disorders of glycosylation type 1a. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Pediatric Metabolic Diseases, Hacettepe University	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	-	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.014%). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 10602363). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.98; 3Cnet: 0.92). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000007716 / PMID: 9497260). Different missense changes at the same codon (p.Thr237Lys, p.Thr237Met) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000021145 / PMID: 28139241, 9140401). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 09, 2016	Variant summary: The PMM2 c.710C>G (p.Thr237Arg) variant causes a missense change involving a conserved nucleotide with 5/5 in silico tools predicting a "damaging" outcome, which PMM2 activity detection levels support this. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 18/120616 (1/6702), which does not exceed the estimated maximal expected allele frequency for a pathogenic PMM2 variant of 1/178. Multiple publications report the variant in compound heterozygote and homozygote affected individuals. In addition, multiple reputable databases and clinical diagnostic laboratories cite the variant as "pathogenic." Therefore, the variant of interest has been classified as "pathogenic." -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 06, 2020	NM_000303.2(PMM2):c.710C>G(T237R) is classified as likely pathogenic in the context of congenital disorder of glycosylation type Ia. Sources cited for classification include the following: PMID 10602363, 17920054, 25355454 and 11058895. Classification of NM_000303.2(PMM2):c.710C>G(T237R) is based on the following criteria: This variant 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. -

not provided

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2021	Published functional studies demonstrate a damaging effect (Kjaergaard et al., 1999); 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: 9497260, 15714316, 11058896, 15844218, 1058895, 11156536, 20638314, 23988505, 10602363, 32304219, 31980526, 33532864, 33413482, 11409861, 34426522, 31589614, 33643843) -
Likely pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 03, 2013	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 09, 2021

The c.710C>G (p.T237R) alteration is located in exon 8 (coding exon 8) of the PMM2 gene. This alteration results from a C to G substitution at nucleotide position 710, causing the threonine (T) at amino acid position 237 to be replaced by an arginine (R). Based on data from gnomAD, the G allele has an overall frequency of 0.01% (39/282470) total alleles studied. The highest observed frequency was 0.03% (38/129066) of European (non-Finnish) alleles. This alteration has been reported presumably in trans with another PMM2 alteration in several unrelated individuals with congenital disorder of glycosylation type 1a (Matthijs, 1998; Kjaergaard, 1999; Le Bizec, 2005; Monin, 2014; Barone, 2015; García-López, 2016). In addition, another alteration at this position (p.T237M) has also been reported (Matthijs, 1997; Vega, 2011). This amino acid position is highly conserved in available vertebrate species. In vitro functional studies of the p.T237R variant in E.coli showed no measurable residual PMM2 activity (Kjaergaard, 1999). 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

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 27, 2024

The PMM2 c.710C>G variant is predicted to result in the amino acid substitution p.Thr237Arg. This variant was reported in the compound heterozygous state in multiple individuals with congenital disorder of glycosylation 1a (Matthijs et al. 1998. PubMed ID: 9497260; Aronica et al. 2005. PubMed ID: 15714316; Starosta et al. 2021. PubMed ID: 33413482; Le Bizec et al. 2005. PubMed ID: 15844218; Barone et al. 2014. PubMed ID: 25355454). This variant is reported in 0.029% of alleles in individuals of European (Non-Finnish) descent in gnomAD. 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

Apr 17, 2020

ACMG classification criteria: PS3, PS4, PM2, PM3, PP2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.57

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.94

D;D;.

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.93

D;D;D

M_CAP

Pathogenic

0.44

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.1

.;H;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-5.5

D;D;D

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

.;D;.

Vest4

0.97

MVP

0.97

MPC

0.046

ClinPred

0.99

GERP RS

5.2

Varity_R

0.99

gMVP

0.98

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

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