rs190521996

Variant names:

• chr16-8811660-T-C
• rs190521996
• NM_000303.3:c.470T>C

Your query was ambiguous. Multiple possible variants found:

• chr16-8811660-T-C
• chr16-8811660-T-G

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000303.3(PMM2):​c.470T>C​(p.Phe157Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000573 in 1,612,830 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F157C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00059 (0 hom.)
• Consequence: PMM2 NM_000303.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:23
• Conservation: PhyloP100: 7.78

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

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

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000303.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-8811660-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1993071.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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 SRD5A3-congenital disorder of glycosylation, PMM2-congenital disorder of glycosylation, congenital disorder of glycosylation type I.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.944
• PP5: Variant 16-8811660-T-C is Pathogenic according to our data. Variant chr16-8811660-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-8811660-T-C is described in Lovd as [Pathogenic]. Variant chr16-8811660-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMM2	NM_000303.3	c.470T>C	p.Phe157Ser	missense_variant	Exon 6 of 8	ENST00000268261.9	NP_000294.1
PMM2	XM_047434215.1	c.221T>C	p.Phe74Ser	missense_variant	Exon 4 of 6		XP_047290171.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMM2	ENST00000268261.9	c.470T>C	p.Phe157Ser	missense_variant	Exon 6 of 8	1	NM_000303.3	ENSP00000268261.4

Frequencies

GnomAD3 genomes AF: 0.000401 AC: 61 AN: 152250 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000617

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000294 AC: 74 AN: 251382 AF XY: 0.000258

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000537

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000591 AC: 863 AN: 1460462 Hom.: 0 Cov.: 29 AF XY: 0.000594 AC XY: 432 AN XY: 726670

Gnomad4 AFR exome AF: 0.0000897 AC: 3 AN: 33456

Gnomad4 AMR exome AF: 0.000268 AC: 12 AN: 44724

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26120

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39684

Gnomad4 SAS exome AF: 0.0000348 AC: 3 AN: 86222

Gnomad4 FIN exome AF: 0.0000187 AC: 1 AN: 53402

Gnomad4 NFE exome AF: 0.000745 AC: 827 AN: 1110742

Gnomad4 Remaining exome AF: 0.000282 AC: 17 AN: 60346

GnomAD4 genome AF: 0.000400 AC: 61 AN: 152368 Hom.: 0 Cov.: 33 AF XY: 0.000416 AC XY: 31 AN XY: 74508

Gnomad4 AFR AF: 0.000216 AC: 0.000216409 AN: 0.000216409

Gnomad4 AMR AF: 0.000523 AC: 0.000522739 AN: 0.000522739

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000617 AC: 0.00061732 AN: 0.00061732

Gnomad4 OTH AF: 0.000945 AC: 0.00094518 AN: 0.00094518

Alfa AF: 0.000419 Hom.: 0

Bravo AF: 0.000370

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000272 AC: 33

EpiCase AF: 0.000436

EpiControl AF: 0.000533

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:23

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PMM2-congenital disorder of glycosylation Pathogenic:12

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Across a selection of the available literature, the PMM2 c.470T>C (p.Phe157Ser) missense variant is reported in a compound heterozygous state with a second variant in eight patients with congenital disorder of glycosylation type 1a (CDG1a), and in one patient where zygosity information is not provided (Matthijs et al. 1999; Briones et al. 2002; Noelle et al. 2005; Romano et al. 2009; Vega et al. 2011; Casado et al. 2012; Resende et al. 2014). Nearly all of these patients exhibited a severe phenotype and residual PMM2 enzyme activity in patient fibroblasts was extremely low or undetectable. Control data are unavailable for this variant, which is reported at a frequency of 0.00081 in the European American population of the Exome Sequencing Project. Analysis of the p.Phe157Ser variant in a prokaryotic expression system showed that the variant affected the stability and structure, and significantly decreased the half-life of the protein (Vega et al. 2011). Based on the collective evidence, the p.Phe157Ser variant is classified as pathogenic for congenital disorders of glycosylation. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Jun 03, 2016

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The PMM2 c.470T>C (p.Phe157Ser) variant causes a missense mutation involving a conserved nucleotide with 5/5 in silico tools predicting a damaging outcome, which functional studies support this prediction. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 33/121274 (1/3675), which does not exceed the estimated maximal expected allele frequency for a pathogenic PMM2 variant of 1/178. (0.0055902). The variant of interest has been reported in multiple affected individuals via publications, along with a reputable clinical laboratory citing the variant as "likely pathogenic." Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as Pathogenic. -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 27, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 07, 2024

Genetics laboratory, Department of Obstetrics & Gynae, Institute of Kidney Diseases & Research Centre Dr. H.L. Trivedi Institute Of Transplantation Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

A heterozygous missense variant c.470T>C in PMM2 gene (chr16:8905517; Depth: 200x) was detected. This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 157 of the PMM2 protein (p.Phe157Ser). This variant is present in population databases (rs190521996, gnomAD 0.06%). This missense change has been observed in individual(s) with congenital disorder of glycosylation type Ia. In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. 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, indicates that this missense variant is expected to disrupt PMM2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PMM2 function. For these reasons, this variant has been classified as pathogenic according to the ACMG guidelines. -

Dec 06, 2022

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PM3_Strong, PP3 -

Dec 11, 2024

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 serine, which is neutral and polar, at codon 157 of the PMM2 protein (p.Phe157Ser). This variant is present in population databases (rs190521996, gnomAD 0.06%). This missense change has been observed in individual(s) with congenital disorder of glycosylation type Ia (PMID: 11156536, 15645285, 19357119, 21541725, 22012410, 24739649, 25355454). 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: 188763). 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%. Experimental studies have shown that this missense change affects PMM2 function (PMID: 21541725). For these reasons, this variant has been classified as Pathogenic. -

Dec 20, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000303.2(PMM2):c.470T>C(F157S) is classified as pathogenic in the context of congenital disorder of glycosylation type Ia. Sources cited for classification include the following: PMID 11156536, 17166182, 12607543, 12705494, 19396570, 17920054, 21541725 and 15645285. Classification of NM_000303.2(PMM2):c.470T>C(F157S) 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. -

Feb 11, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 24, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) 0115 - Variants in this gene are known to have variable expressivity. The clinical manifestations and course are highly variable, ranging from infants who die in the first year of life to mildly affected adults. (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from phenylalanine to serine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 91 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in at least twenty individuals with congenital disorder of glycosylation, including compound heterozygotes (PMID: 33340551). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 22, 2020

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided Pathogenic:8

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 15, 2021

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 05, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate this variant results in complete loss of enzyme activity and may impact the stability and/or structure of the protein (Romano et al., 2009; Vega et al., 2011); 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: 17166182, 15844218, 15645285, 29482223, 11343337, 18948042, 19396570, 22012410, 19357119, 10527672, 11156536, 24739649, 28373276, 17920054, 12705494, 12607543, 23430838, 17158594, 25497157, 25355454, 21541725, 32304219, 32630370, 32841164, 33643843, 33413482, 31589614, 34598035, 33580824, 35279850, 33340551) -

May 13, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PS4, PM2, PM3_strong, PP3, PP4 -

Nov 15, 2021

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the PMM2 gene demonstrated a sequence change, c.470T>C, in exon 6 that results in an amino acid change, p.Phe157Ser. This sequence change has been described in the gnomAD database with a frequency of 0.06% in the non-Finnish European subpopulation (dbSNP rs190521996). This sequence change has been described in the compound heterozygous state with other pathogenic/likely pathogenic variants in individuals with PMM2-related disorder (PMIDs: 24739649, 15645285, 11156536, 19357119, 25355454, 22012410). The p.Phe157Ser change affects a highly conserved amino acid residue located in the cap domain of the PMM2 protein. The p.Phe157Ser substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Functional studies suggest p.Phe157Ser disrupts the stability and activity of the PMM2 protein (PMID: 21541725). Collectively, this evidence suggests p.Phe157Ser is likely pathogenic. -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PMM2: PM3:Very Strong, PM2, PS3:Supporting -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Jan 09, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.470T>C (p.F157S) alteration is located in exon 6 (coding exon 6) of the PMM2 gene. This alteration results from a T to C substitution at nucleotide position 470, causing the phenylalanine (F) at amino acid position 157 to be replaced by a serine (S). Based on data from gnomAD, the C allele has an overall frequency of 0.032% (91/282784) total alleles studied. The highest observed frequency was 0.06% (77/129118) of European (non-Finnish) alleles. This variant has been identified in conjunction with other PMM2 variant(s) in individual(s) with features consistent with PMM2-related congenital disorder of glycosylation (Grunewald, 2001; Briones, 2002; Noelle, 2005; Vega, 2011; Casado, 2012; Monin, 2014; Resende, 2014; Barone, 2015; Serrano, 2015; Starosta, 2021; Bakar, 2022). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

PMM2-related disorder Pathogenic:1

Jul 11, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PMM2 c.470T>C variant is predicted to result in the amino acid substitution p.Phe157Ser. This variant has been documented in many unrelated individuals to be causative for autosomal recessive congenital disorders of glycosylation type Ia due to abolished phosphomannomutase 2 enzyme activity (Matthijs et al. 1999. PubMed ID: 10527672; Vega et al. 2011. PubMed ID: 21541725; Resende et al. 2014. PubMed ID: 24739649). It has been interpreted as pathogenic or likely pathogenic by many independent submitters to ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/188763/). This variant is reported in 0.060% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Taken together, this variant is interpreted as pathogenic. -

See cases Pathogenic:1

Jan 29, 2021

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PS3, PS4, PM3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;D;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	.;H;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-6.1	D;D;D
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.98
MVP		0.98
MPC		0.041
ClinPred		0.95	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.99
gMVP		0.96
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.020		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: rs190521996; hg19: chr16-8905517;