16-8813090-G-C

Variant summary

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

The NM_000303.3(PMM2):​c.623G>C​(p.Gly208Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000876 in 1,597,560 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 (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000090 ( 0 hom. )

Consequence

PMM2
NM_000303.3 missense

Scores

15
3
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 9.48
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]

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, 0.994
PP5
Variant 16-8813090-G-C is Pathogenic according to our data. Variant chr16-8813090-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 92804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-8813090-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PMM2NM_000303.3 linkc.623G>C p.Gly208Ala missense_variant Exon 7 of 8 ENST00000268261.9 NP_000294.1 O15305-1A0A0S2Z4J6Q59F02
PMM2XM_047434215.1 linkc.374G>C p.Gly125Ala missense_variant Exon 5 of 6 XP_047290171.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PMM2ENST00000268261.9 linkc.623G>C p.Gly208Ala missense_variant Exon 7 of 8 1 NM_000303.3 ENSP00000268261.4 O15305-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152158
Hom.:
0
Cov.:
33
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:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000899
AC:
13
AN:
1445402
Hom.:
0
Cov.:
27
AF XY:
0.00000416
AC XY:
3
AN XY:
720378
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:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000912
Gnomad4 OTH exome
AF:
0.0000334
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152158
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74344
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000557
Hom.:
0
Bravo
AF:
0.00000378
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

PMM2-congenital disorder of glycosylation Pathogenic:7
Jul 17, 2023
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_v1.3.4, 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 pass away in the first year of life to mildly affected adults (PMID: 20301289). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to alanine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (1 heterozygote, 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 eukaryotic phosphomannomutase domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic and pathogenic by multiple clinical laboratories in ClinVar, and has been observed in individuals with CDG who also had another PMM2 variant, three of whom were known to be compound heterozygous (PMIDs: 22649348, 10801058, 28122681, 30397276). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Aug 13, 2018
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant has been previously reported in the compound heterozygous state in individuals with Congenital disorder of glycosylation Type 1A (PMID: 9497260, 19396570, 10801058) and has been classified as pathogenic and likely pathogenic by multiple clinical diagnostic laboratories in ClinVar (Variation ID: 92804). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. The c.623G>C (p.Gly208Ala) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.623G>C (p.Gly208Ala) variant is classified as Likely Pathogenic. -

May 16, 2016
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.623G>C (p.Gly208Ala) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome. This variant was found in 1/121408 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic PMM2 variant (0.005902). This variant has been reported in multiple CDG1A patients homozygously or as a compound heterozygotes with a pathogenic variant (such as R141H) in trans. All reported patients had very low level of PMM activity detected. In addition, one clinical diagnostic laboratory classified this variant as pathogenic. Considering all, this variant is classified as pathogenic. -

Dec 24, 2023
Baylor Genetics
Significance: Likely 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

- -

Feb 24, 2017
Counsyl
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 14, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 208 of the PMM2 protein (p.Gly208Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with PMM2-CDG (PMID: 9497260, 10801058, 15277997, 24037084). ClinVar contains an entry for this variant (Variation ID: 92804). 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%. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1
Feb 05, 2013
Eurofins Ntd Llc (ga)
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
0.97
BayesDel_addAF
Pathogenic
0.58
D
BayesDel_noAF
Pathogenic
0.60
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.94
D;D;.
Eigen
Pathogenic
0.92
Eigen_PC
Pathogenic
0.83
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
1.0
D;D;D
M_CAP
Pathogenic
0.79
D
MetaRNN
Pathogenic
0.99
D;D;D
MetaSVM
Pathogenic
0.85
D
MutationAssessor
Pathogenic
4.1
.;H;.
PrimateAI
Uncertain
0.71
T
PROVEAN
Pathogenic
-5.8
D;D;D
REVEL
Pathogenic
0.98
Sift
Pathogenic
0.0
D;D;D
Sift4G
Uncertain
0.012
D;D;D
Polyphen
1.0
.;D;.
Vest4
0.99
MutPred
0.97
.;Gain of catalytic residue at G208 (P = 0.0103);.;
MVP
0.98
MPC
0.046
ClinPred
1.0
D
GERP RS
4.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.99
gMVP
0.98

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
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.

Other links and lift over

dbSNP: rs398123309; hg19: chr16-8906947; API