rs150719105

Positions:

• chr16-8811161-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 13P and 1B. PM1 PM2 PP3 PP5_Very_Strong BP4

The NM_000303.3(PMM2):​c.430T>C​(p.Phe144Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000338 in 1,566,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: PMM2 NM_000303.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 7.85

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 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: Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, M_CAP, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• PP5: Variant 16-8811161-T-C is Pathogenic according to our data. Variant chr16-8811161-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 197658.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-8811161-T-C is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.1515708). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMM2	NM_000303.3	c.430T>C	p.Phe144Leu	missense_variant	5/8	ENST00000268261.9	NP_000294.1
PMM2	XM_047434215.1	c.181T>C	p.Phe61Leu	missense_variant	3/6		XP_047290171.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PMM2	ENST00000268261.9	c.430T>C	p.Phe144Leu	missense_variant	5/8	1	NM_000303.3	ENSP00000268261.4

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152154 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000165 AC: 31 AN: 188306 Hom.: 0 AF XY: 0.000119 AC XY: 12 AN XY: 100472

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000687

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00200

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000290 AC: 41 AN: 1414502 Hom.: 0 Cov.: 30 AF XY: 0.0000228 AC XY: 16 AN XY: 700236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000994

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000977

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152272 Hom.: 0 Cov.: 34 AF XY: 0.0000806 AC XY: 6 AN XY: 74454

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00231

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000680

ExAC AF: 0.000121 AC: 14

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PMM2-congenital disorder of glycosylation Pathogenic:6

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 30, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 26, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 06, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 144 of the PMM2 protein (p.Phe144Leu). This variant is present in population databases (rs150719105, gnomAD 0.2%). This missense change has been observed in individual(s) with PMM2-related disease (PMID: 10066032, 28122681, 30687093). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 197658). 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%. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Apr 18, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 07, 2024	Variant summary: PMM2 c.430T>C (p.Phe144Leu) 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 0.00016 in 188306 control chromosomes (gnomAD). This frequency is not higher than the estimated maximum expected for a pathogenic variant in PMM2 causing Congenital Disorder Of Glycosylation Type 1a (0.0056), allowing no conclusion about variant significance. c.430T>C has been reported in the literature in multiple compound heterozygous individuals affected with Congenital Disorder Of Glycosylation Type 1a (e.g. Kondo_1999, At Teneji_2017, Wang 2019, Lin 2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28122681, 32635232, 10066032, 10392743, 33176815, 30687093). ClinVar contains an entry for this variant (Variation ID: 197658). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 28, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 18, 2016	The F144L variant has previously been reported in unrelated individuals with congenital disorder of glycosylation type 1a (CDG-1a) who were heterozygous for F144L and another missense variant in the PMM2 gene, although the phase of these variants was not reported (Kondo et al., 1999; Kane et al., 2016). The 1000 Genomes Project Consortium reports F144L was observed in 2/1008 alleles from individuals of East Asian background. The F144L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (E139K, R141H, D148N) have been reported in the Human Gene Mutation Database in association with CDG-1a (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.29	D
MetaRNN	Benign	0.15	T;T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	.;H
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-5.8	D;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.011	D;D
Polyphen		0.97	.;D
Vest4		0.98
MutPred		0.98		.;Gain of catalytic residue at F144 (P = 0.0814);
MVP		0.98
MPC		0.013
ClinPred		0.42	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.88

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

Other links and lift over

dbSNP: rs150719105; hg19: chr16-8905018;