rs80338703

chr16-8811146-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000303.3(PMM2):c.415G>A(p.Glu139Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000014 in 1,423,654 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PMM2 NM_000303.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9 O:1
• Conservation: PhyloP100: 5.49

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 16 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000303.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.946
• PP5: Variant 16-8811146-G-A is Pathogenic according to our data. Variant chr16-8811146-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 21143.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMM2	NM_000303.3	c.415G>A	p.Glu139Lys	missense_variant	5/8	ENST00000268261.9
PMM2	XM_047434215.1	c.166G>A	p.Glu56Lys	missense_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMM2	ENST00000268261.9	c.415G>A	p.Glu139Lys	missense_variant	5/8	1	NM_000303.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1423654 Hom.: 0 Cov.: 31 AF XY: 0.00000142 AC XY: 1 AN XY: 704786

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000261

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.18e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PMM2-congenital disorder of glycosylation Pathogenic:6 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	May 25, 2017	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 08, 2023	For these reasons, this variant has been classified as Pathogenic. Studies have shown that this missense change is associated with altered splicing resulting in multiple RNA products (PMID: 10571956). Experimental studies have shown that this missense change affects PMM2 function (PMID: 10571956). 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. ClinVar contains an entry for this variant (Variation ID: 21143). This missense change has been observed in individual(s) with congenital disorder of glycosylation type 1a (PMID: 10571956). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 139 of the PMM2 protein (p.Glu139Lys). -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 09, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Oct 02, 2021	The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (VCV000021143.5, PMID: 15844218, 19357119, PM3_S). It is not observed in the gnomAD v2.1.1 dataset (PM2). Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 15844218). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.701, 3Cnet: 0.940, PP3). Patient's phenotype is considered compatible with Congenital disorder of glycosylation, type Ia (3billion dataset, PP4). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	research	Dobyns Lab, Seattle Children's Research Institute	Feb 18, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 30, 2018	Variant summary: PMM2 c.415G>A (p.Glu139Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. At least one publication reports experimental evidence that this variant affects mRNA splicing, resulting in exon 5 skipping (Vuillaumier-Barrot_1999). The variant was absent in 189894 control chromosomes (gnomAD). The variant, c.415G>A, has been reported in the literature in multiple individuals affected with Congenital Disorder of Glycosylation Type 1a and was reported to be a founder mutation in the French population (Vuillaumier-Barrot_1999, LeBizec_2005). These data indicate that the variant is very likely to be associated with disease. Two publications from the same group report experimental evidence evaluating an impact on protein function (Vuillaumier-Barrot_1999, LeBizec_2005). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 09, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 07, 2017	The E139K variant in the PMM2 gene has been reported previously numerous times in association with CDG type 1a (Vullamier-Barrot et al., 1999; Le Bizec et al., 2005; Romano et al., 2009). Functional studies demonstrate that this variant disrupts a splicing enhancer sequence, which causes skipping of exon 5 and ultimately results in decreased protein activity (Vullamier-Barrot et al., 1999; Le Bizec et al., 2005; Smith et al., 2006). The E139K variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant is a non-conservative amino acid substitution, which occurs at a position that is conserved across species. Missense variants in nearby residues (R141C, R141H, F144L) have been reported in the Human Gene Mutation Database in association with CDG type 1a (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret E139K as a pathogenic variant. -

Congenital cerebellar hypoplasia Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D;D
Eigen	Benign	0.015
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Pathogenic	0.91	D
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-2.1	N;N
Sift	Benign	0.11	T;T
Sift4G	Benign	0.24	T;T
Polyphen		0.069	.;B
Vest4		0.92
MutPred		0.86		.;Gain of ubiquitination at E139 (P = 0.0117);
MVP		0.91
MPC		0.019
ClinPred		0.89	D
GERP RS		5.4
Varity_R		0.79
gMVP		0.82

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

Other links and lift over

dbSNP: rs80338703; hg19: chr16-8905003;