NM_000303.3:c.430T>C

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 13P and 1B. PM1PM2PP3PP5_Very_StrongBP4

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

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 7.85

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
PMM2	NM_000303.3 link	c.430T>C	p.Phe144Leu	missense_variant	Exon 5 of 8	ENST00000268261.9	NP_000294.1	O15305-1A0A0S2Z4J6Q59F02
PMM2	XM_047434215.1 link	c.181T>C	p.Phe61Leu	missense_variant	Exon 3 of 6		XP_047290171.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMM2	ENST00000268261.9 link	c.430T>C	p.Phe144Leu	missense_variant	Exon 5 of 8	1	NM_000303.3	ENSP00000268261.4		O15305-1

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152154

Hom.:

Cov.:

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:

0.00231

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:

AN:

188306

Hom.:

AF XY:

0.000119

AC XY:

AN XY:

100472

show subpopulations

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:

AN:

1414502

Hom.:

Cov.:

AF XY:

0.0000228

AC XY:

AN XY:

700236

show subpopulations

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:

AN:

152272

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74454

show subpopulations

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:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

PMM2-congenital disorder of glycosylation

Pathogenic:8

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM3_VeryStrong+PP3_Strong+PP1_Moderate -

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). 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. -

Feb 10, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 30, 2023

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 26, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 07, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Oct 28, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PMM2 c.430T>C; p.Phe144Leu variant (rs150719105, ClinVar Variation ID: 197658) is reported in the literature in individuals affected with congenital disorder of glycosylation, including individuals who also carry a pathogenic variant in trans (Kane 2016, Kondo 1999, Lin 2020). This variant is found in the general population with an overall allele frequency of 0.02% (37/219716 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses predict that this variant is deleterious REVEL: 0.956). Based on available information, this variant is considered to be likely pathogenic. References: Kane MS et al. Mitotic Intragenic Recombination: A Mechanism of Survival for Several Congenital Disorders of Glycosylation. Am J Hum Genet. 2016 Feb 4;98(2):339-46. PMID: 26805780. Kondo I et al. Missense mutations in phosphomannomutase 2 gene in two Japanese families with carbohydrate-deficient glycoprotein syndrome type 1. Clin Genet. 1999 Jan;55(1):50-4. PMID: 10066032. Lin L et al. Clinical and genetic characteristics and prenatal diagnosis of patients presented GDD/ID with rare monogenic causes. Orphanet J Rare Dis. 2020 Nov 11;15(1):317. PMID: 33176815. -

Apr 18, 2017

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Pathogenic:2

Nov 18, 2016

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 28, 2017

Eurofins Ntd Llc (ga)

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.93

D;D

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Pathogenic

0.29

MetaRNN

Benign

0.15

T;T

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.0

.;H

PrimateAI

Uncertain

0.71

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

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

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