16-8811161-T-C

Variant names:

• chr16-8811161-T-C
• rs150719105
• NM_000303.3:c.430T>C

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 18P and 1B. PS1 PM1 PM5 PP2 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 (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F144V) has been classified 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:11
• Conservation: PhyloP100: 7.85
• Publications: 13 publications found

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 Gene-Disease associations (from GenCC):

• congenital disorder of glycosylation type I

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
• PMM2-congenital disorder of glycosylation

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia, ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PS1: Transcript NM_000303.3 (PMM2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000303.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-8811161-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2185603.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 89 curated pathogenic missense variants (we use a threshold of 10). The gene has 24 curated benign missense variants. Gene score misZ: -1.3872 (below the threshold of 3.09). Trascript score misZ: -1.8083 (below the threshold of 3.09). GenCC associations: The gene is linked to PMM2-congenital disorder of glycosylation, congenital disorder of glycosylation type I.
• PP3: Multiple lines of computational evidence support a deleterious effect 10: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, M_CAP, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL, 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 197658.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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	c.430T>C	p.Phe144Leu	missense_variant	Exon 5 of 8	ENST00000268261.9	NP_000294.1
PMM2	XM_047434215.1	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	c.430T>C	p.Phe144Leu	missense_variant	Exon 5 of 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

GnomAD2 exomes AF: 0.000165 AC: 31 AN: 188306 AF XY: 0.000119

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 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

African (AFR) AF: 0.00 AC: 0 AN: 32322

American (AMR) AF: 0.0000994 AC: 4 AN: 40230

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25448

East Asian (EAS) AF: 0.000977 AC: 37 AN: 37860

South Asian (SAS) AF: 0.00 AC: 0 AN: 81456

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50442

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5712

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1082592

Other (OTH) AF: 0.00 AC: 0 AN: 58440

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

African (AFR) AF: 0.00 AC: 0 AN: 41534

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00231 AC: 12 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000680

ExAC AF: 0.000121 AC: 14

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PMM2-congenital disorder of glycosylation Pathogenic:9

Mar 26, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 10, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For recessive disorders, detected in trans with a pathogenic variant.;Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc).;Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.

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

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Nov 23, 2023

Department of Rehabilitation, Anhui Provincial Children's Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is a missense mutation. REVEL prediction results suggest that this variant has a damaging effect on the gene or gene product.

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.

Jul 10, 2025

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. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant allele was found at a frequency of 0.00016 in 188306 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in PMM2 causing Congenital Disorder Of Glycosylation Type 1a (0.00016 vs 0.0056), allowing no conclusion about variant significance. c.430T>C has been observed in multiple individuals affected with Congenital Disorder Of Glycosylation Type 1a (Kondo_1999, Al Teneiji_2017, Lin_2020, Wang_2019). 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, 33176815, 10392743, 30687093). ClinVar contains an entry for this variant (Variation ID: 197658). Based on the evidence outlined above, the variant was classified as pathogenic.

Mar 30, 2023

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

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	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	Benign	0.0	.;H
PhyloP100		7.9
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-5.8	D;D
REVEL	Benign	0.0
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.011	D;D
Vest4		0.98
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
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs150719105; hg19: chr16-8905018;