16-8847794-C-T

Position:

chr16-8847794-C-T

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>T(p.Thr237Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000198 in 1,613,470 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 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

PMM2
NM_000303.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17O:1

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, 0.995

PP5

Variant 16-8847794-C-T is Pathogenic according to our data. Variant chr16-8847794-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 21145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-8847794-C-T 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>T	p.Thr237Met	missense_variant	8/8	ENST00000268261.9	NP_000294.1
PMM2	XM_047434215.1 linkuse as main transcript	c.461C>T	p.Thr154Met	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>T	p.Thr237Met	missense_variant	8/8	1	NM_000303.3	ENSP00000268261	P1	O15305-1
	ENST00000567942.1 linkuse as main transcript	n.286G>A		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000438

AC:

AN:

251084

Hom.:

AF XY:

0.0000516

AC XY:

AN XY:

135728

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.0000467

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1461276

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

726976

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.00000900

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:17Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

PMM2-congenital disorder of glycosylation

Pathogenic:9Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 18, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 27, 2020	Variant summary: PMM2 c.710C>T (p.Thr237Met) 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 4.4e-05 in 251084 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in PMM2 causing Congenital Disorder of Glycosylation Type 1a (4.4e-05 vs 0.0056), allowing no conclusion about variant significance. c.710C>T has been reported in the literature in multiple individuals affected with Congenital Disorder of Glycosylation Type 1a (example, Matthijs_1997, Briones_2001, Tayebi_2002, Bortot_2013, Vega_2011). These data indicate that the variant is very likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal activity due to a destabilizing outcome on folding (example Vega_2011 and Yuste-Checa_2015). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=5)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	Sep 22, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 22, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	The variant c.710C>T has been reported in a homozygous state in similarly affected individuals with congenital disorder of glycosylation, type Ia earlier (Matthijs et al., 1997). This variant was also reported in the ClinVar database as a likely pathogenic/pathogenic variant in 17 independent submissions (ClinVar ID: 21145). In silico prediction tools (MutationTaster, CADD phred, and REVEL) are consistent in predicting the variant to be damaging to PMM2 protein function. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 23, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 26, 2023	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Feb 06, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 22, 2023	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 237 of the PMM2 protein (p.Thr237Met). This variant is present in population databases (rs80338708, gnomAD 0.01%). This missense change has been observed in individual(s) with congenital disorder of glycosylation type 1 (PMID: 11589167, 11891694, 21541725, 23430838, 23988505). 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: 21145). 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, 26014514). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 24, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 13, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 21, 2020	PS3, PS4, PM2, PM3, PM5, PP3, PP4, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 01, 2022	Published functional studies demonstrate a reduced residual activity in T237M when compared with wild type, and T237M was identified as destabilizing variant (Vega et al., 2011; Yuste-Checa et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); 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: 10801058, 28685491, 11589167, 21541725, 9140401, 23988505, 11891694, 26014514, 15844218, 11156536, 11058895, 27774737, 19235233, 28425223, 12705494, 31736265, 33413482) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	PMM2: PM3:Very Strong, PM2, PM5, PP4:Moderate, PS3:Supporting -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 27, 2017

- -

PMM2-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 19, 2024

The PMM2 c.710C>T variant is predicted to result in the amino acid substitution p.Thr237Met. This variant has been documented as causative for autosomal recessive congenital disorder of glycosylation type Ia when present with a second causative variant (Matthijs et al. 1997. PubMed ID: 9140401; Tayebi et al. 2002. PubMed ID: 11891694; Bortot et al. 2013. PubMed ID: 23988505). Functional studies have shown that the p.Thr237Met substitution causes a partial decrease in protein abundance and residual enzymatic activity, and the authors suggest a mild classification for this variant (Vega et al. 2011. PubMed ID: 21541725; Yuste-Checa et al. 2015. PubMed ID: 26014514). This variant is reported in 0.013% of alleles in individuals of South Asian descent in gnomAD. Given the evidence, we interpret c.710C>T (p.Thr237Met) as pathogenic. -

Intellectual disability

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Diagnostic Laboratory, Strasbourg University Hospital

Apr 20, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.75

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

D;D;.

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.96

D;D;D

M_CAP

Pathogenic

0.44

MetaRNN

Pathogenic

1.0

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.1

.;H;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-5.6

D;D;D

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

.;D;.

Vest4

0.96

MutPred

0.95

.;Loss of phosphorylation at T237 (P = 0.029);.;

MVP

0.97

MPC

0.047

ClinPred

0.99

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.94

gMVP

0.93

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