rs141498002

chr16-8811099-G-Achr16-8811099-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_000303.3(PMM2):c.368G>A(p.Arg123Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000268 in 1,571,002 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 0.00016 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00028 (0 hom.)
• Consequence: PMM2 NM_000303.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 9.79

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000303.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.918
• PP5: Variant 16-8811099-G-A is Pathogenic according to our data. Variant chr16-8811099-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 265255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-8811099-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMM2	NM_000303.3	c.368G>A	p.Arg123Gln	missense_variant	5/8	ENST00000268261.9
PMM2	XM_047434215.1	c.119G>A	p.Arg40Gln	missense_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMM2	ENST00000268261.9	c.368G>A	p.Arg123Gln	missense_variant	5/8	1	NM_000303.3	P1

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152180 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000114 AC: 22 AN: 192596 Hom.: 0 AF XY: 0.000127 AC XY: 13 AN XY: 102744

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000134

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000133

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000568

Gnomad NFE exome AF: 0.000191

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000279 AC: 396 AN: 1418822 Hom.: 0 Cov.: 31 AF XY: 0.000271 AC XY: 190 AN XY: 702024

Gnomad4 AFR exome AF: 0.0000616

Gnomad4 AMR exome AF: 0.000223

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000132

Gnomad4 SAS exome AF: 0.0000123

Gnomad4 FIN exome AF: 0.000198

Gnomad4 NFE exome AF: 0.000332

Gnomad4 OTH exome AF: 0.000137

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152180 Hom.: 0 Cov.: 34 AF XY: 0.000148 AC XY: 11 AN XY: 74334

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00143

Alfa AF: 0.000113 Hom.: 0

Bravo AF: 0.000212

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ExAC AF: 0.0000850 AC: 10

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PMM2-congenital disorder of glycosylation Pathogenic:10

Pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Sep 10, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 123 of the PMM2 protein (p.Arg123Gln). This variant is present in population databases (rs141498002, gnomAD 0.02%). This missense change has been observed in individual(s) with PMM2-CDG (PMID: 9497260, 15844218, 21541725, 22012410). 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: 265255). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PMM2 protein function. Experimental studies have shown that this missense change affects PMM2 function (PMID: 21541725, 26014514). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 04, 2016	Variant summary: The PMM2 c.368G>A (p.Arg123Gln) variant involves the alteration of a conserved nucleotide. 4/5 in silico tools predict a deleterious outcome. This variant was found in 3/28750 control chromosomes at a frequency of 0.0001043, which does not exceed the estimated maximal expected allele frequency of a pathogenic PMM2 variant (0.0055902). This variant has been reported in many CDG patients as compound heterozygotes with another pathogenic variant in trans. Functional studies showed that variant of interest led to null activity of the protein and classified the variant as one of the severe mutations. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 28, 2017	- -
Likely pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Aug 29, 2018	ACMG codes: PS3, PM2, PP3, PP5 -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 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) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 – This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (30 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position to leucine 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 Phosphomannomutase annotated domain (NCBI). (I) 0801 – This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has been previously reported as pathogenic in patients with congenital disorder of glycosylation type Ia (ClinVar, PMID: 9497260, 15844218, 22012410). (SP) 1102 - Strong phenotype match for this individual. (SP) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 16, 2018	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 9497260, 22012410, 10527672, 21541725, 28807751, 26014514] -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 24, 2019	NM_000303.2(PMM2):c.368G>A(R123Q) is classified as pathogenic in the context of congenital disorder of glycosylation type Ia. Sources cited for classification include the following: PMID 15844218, 11156536, 21541725, 11409861, 25497157, 17166182, 25355454 and 11715002. Classification of NM_000303.2(PMM2):c.368G>A(R123Q) 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. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 19, 2023	Published functional studies demonstrate that R123Q affects protein stability, causes a 40% reduction of the protein half-life and results in no residual enzyme activity (Vega et al, 2011; Yuste-Checa et al., 2015); 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: 21541725, 28807751, 30304743, 28671287, 34930662, 22012410, 26014514, 11156536, 11715002, 9497260, 10527672, 31115488, 28915903, 25497157, 25355454, 17166182, 15844218, 11409861, 28122681, 10922383, 20652024, 12705494, 32071842) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 08, 2019	PS3, PS4_Moderate, PM2, PP3, PP4 -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 28, 2022

The c.368G>A (p.R123Q) alteration is located in exon 5 (coding exon 5) of the PMM2 gene. This alteration results from a G to A substitution at nucleotide position 368, causing the arginine (R) at amino acid position 123 to be replaced by a glutamine (Q). Based on data from gnomAD, the A allele has an overall frequency of 0.01% (30/223998) total alleles studied. The highest observed frequency was 0.02% (18/94022) of European (non-Finnish) alleles. This mutation has been reported in conjunction with multiple PMM2 missense alterations in individuals with PMM2-related congenital disorder of glycosylation (Matthijs, 1998; Westphal, 2001; Le Bizec, 2005; Vega, 2011)._x000D_ _x000D_ Reference:_x000D_ _x000D_ Westphal V, et al. Genet Med. Nov-Dec 2001;3(6):393-8. This amino acid position is highly conserved in available vertebrate species. Analysis of this variant in both E. coli and S. cerevisiae demonstrated reduced or absent residual activity when compared to wildtype (Westphal, 2001; Vega, 2011; Yuste-Checa, 2015). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.59
Cadd	Pathogenic	34
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.94	D;D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.8	D;D
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.045	D;D
Polyphen		1.0	.;D
Vest4		1.0
MVP		0.98
MPC		0.041
ClinPred		0.97	D
GERP RS		5.4
Varity_R		0.93
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

Other links and lift over

dbSNP: rs141498002; hg19: chr16-8904956;