dbSNP rs28936415: PMM2:p.Arg141His (chr16-8811153-G-A) – ACMG Classification: Pathogenic (19 pts)

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 20P and 1B. PS3PM1PM2PM5PP2PP3PP5_Very_StrongBP4

The NM_000303.3(PMM2):c.422G>A(p.Arg141His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0049 in 1,570,944 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 Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000399674: When expressed in vitro, the residual activity of the p.Arg141His recombinant protein is almost zero and thus supports the inference that homozygosity for this mutation is lethal early in development. This variant also shows a decreased binding affinity for the normal substrate and results in a significantly less stable protein compared to wild type (Pirard et al. 1999)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R141L) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0037 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0050 ( 0 hom. )

Consequence

PMM2
NM_000303.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:64O:3

Conservation

PhyloP100: 9.79

Publications

159 publications found

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 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: Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)
hyperinsulinemic hypoglycemia with polycystic kidney disease
Inheritance: AR Classification: MODERATE Submitted by: ClinGen

PMM2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 19 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000399674: When expressed in vitro, the residual activity of the p.Arg141His recombinant protein is almost zero and thus supports the inference that homozygosity for this mutation is lethal early in development. This variant also shows a decreased binding affinity for the normal substrate and results in a significantly less stable protein compared to wild type (Pirard et al. 1999).; SCV000633725: Experimental studies have shown that this missense change affects PMM2 function (PMID: 21541725, 26014514).; SCV000696497: The most pronounced variant effect results in a loss of PMM2 enzyme activity in one study (example, Vega_2011) and an oligomerization profile with a predominant aggregate fraction, less dimerization, nearly non-detectable enzymatic activities, and shorter degradation time in another study (example, Yuste-Checa_2015).; SCV000711768: In vitro functional studies provide evidence that this variant causes complete loss of enzyme activity (Vega 2011 PMID: 21541725, Andreotti 2015 PMID: 26488408).; SCV000996184: Functional characterization in multiple studies indicates that the p.Arg141His variant negatively impacts protein function including stability and enzymatic activity (PMID: 21541725, 26488408, 26014514).; SCV002070493: Functional studies have also demonstrated that the p.Arg141His change reduces protein stability and enzymatic activity in vitro (PMID: 26014514); SCV002557015: Functional studies have demonstrated reduced enzyme stability and catalytic activity compared with wild type (PMID:21541725) (PS3).; SCV003841397: "Functional studies provide supporting evidence of the variant having a damaging effect on the gene or gene product (PMID: 26014514)."; SCV003920332: Functional studies support that this variant will impact the protein by affecting folding and catalytic activity (Vega 2011 PMID:21541725, Yuste-Checa 2015 PMID:26014514).; SCV005047051: "In support of this prediction, functional studies show that the p.Arg141His variant affects protein stability, indicating that this variant impacts protein function (Vega AI et al., PMID: 21541725; Yuste-Checa P et al., PMID: 26014514)."; SCV005877341: "Consistent with these observations, functional studies suggest the residual enzymatic activity of the p.Arg141His variant protein is close to zero (Vega 2011)." PMID: 21541725; SCV000321929: Published functional studies demonstrate a damaging effect with reduced enzyme stability and catalytic activity below detection limits (PMID: 21541725); SCV001554206: Functional studies have demonstrated loss of PMM2 protein activity from the p.R141H variant (Vega_2011_PMID:21541725; Yuste-Checa_2015_PMID:26014514).; SCV001712854: PS3; SCV000741460: Functional analysis demonstrated that the PMM2 protein product harboring the p.R141H alteration has no residual enzymatic activity when expressed in vitro. Further, the p.R141H protein product had a shortened half-life compared to wild type protein, suggesting that the alteration affects protein stability (Vega, 2011).; SCV001142455: Functional studies demonstrate that p.Arg141His has reduced protein stability and enzymatic activity in vitro (PMID: 26014514).; SCV002526393: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 21541725, 26488408, 26014514) - PS3."; SCV004739486: Functional in vitro studies on this variant have demonstrated that it severely impacts protein stability and activity (Vega et al. 2011. PubMed ID: 21541725).; SCV005382600: Functional studies support this (PMID 21541725).

PM1

In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_000303.3

PM2

Variant has high frequency in the NFE (0.00557) population. However there is too low homozygotes in high coverage region: (expected more than 9, got 0).

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-8811153-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3251545.

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, hyperinsulinemic hypoglycemia with polycystic kidney disease.

PP3

Multiple lines of computational evidence support a deleterious effect 11: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Dann, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

PP5

Variant 16-8811153-G-A is Pathogenic according to our data. Variant chr16-8811153-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 7706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.020802349). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000303.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMM2	NM_000303.3	MANE Select	c.422G>A	p.Arg141His	missense	Exon 5 of 8	NP_000294.1	A0A0S2Z4J6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PMM2	ENST00000268261.9	TSL:1 MANE Select	c.422G>A	p.Arg141His	missense	Exon 5 of 8	ENSP00000268261.4	O15305-1
PMM2	ENST00000565221.5	TSL:1	n.*40G>A		non_coding_transcript_exon	Exon 3 of 6	ENSP00000457932.1	H3BV34
PMM2	ENST00000567697.2	TSL:1	n.3590G>A		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes

AF:

0.00366

AC:

557

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000893

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00406

Gnomad ASJ

AF:

0.00576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00772

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00509

Gnomad OTH

AF:

0.00334

GnomAD2 exomes

AF:

0.00407

AC:

785

AN:

192974

AF XY:

0.00419

show subpopulations

Gnomad AFR exome

AF:

0.000917

Gnomad AMR exome

AF:

0.00205

Gnomad ASJ exome

AF:

0.00770

Gnomad EAS exome

AF:

0.000133

Gnomad FIN exome

AF:

0.00824

Gnomad NFE exome

AF:

0.00568

Gnomad OTH exome

AF:

0.00468

GnomAD4 exome

AF:

0.00503

AC:

7141

AN:

1418658

Hom.:

Cov.:

AF XY:

0.00489

AC XY:

3432

AN XY:

702556

show subpopulations

African (AFR)

AF:

0.000677

AC:

AN:

32484

American (AMR)

AF:

0.00184

AC:

AN:

40844

Ashkenazi Jewish (ASJ)

AF:

0.00703

AC:

179

AN:

25462

East Asian (EAS)

AF:

0.0000525

AC:

AN:

38126

South Asian (SAS)

AF:

0.000867

AC:

AN:

81898

European-Finnish (FIN)

AF:

0.00770

AC:

390

AN:

50620

Middle Eastern (MID)

AF:

0.000175

AC:

AN:

5722

European-Non Finnish (NFE)

AF:

0.00569

AC:

6175

AN:

1084906

Other (OTH)

AF:

0.00386

AC:

226

AN:

58596

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

320

639

959

1278

1598

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

248

496

744

992

1240

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00366

AC:

557

AN:

152286

Hom.:

Cov.:

AF XY:

0.00388

AC XY:

289

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.000891

AC:

AN:

41536

American (AMR)

AF:

0.00405

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00576

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.000415

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00772

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00509

AC:

346

AN:

68028

Other (OTH)

AF:

0.00331

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

105

131

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00495

Hom.:

Bravo

AF:

0.00349

TwinsUK

AF:

0.00620

AC:

ALSPAC

AF:

0.00727

AC:

ESP6500AA

AF:

0.000910

AC:

ESP6500EA

AF:

0.00536

AC:

ExAC

AF:

0.00295

AC:

346

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

PMM2-congenital disorder of glycosylation (46)

not provided (12)

Cerebellar ataxia (1)

Cerebellar ataxia;C0007789:Cerebral palsy;C0026838:Spasticity;C0235946:Cerebral atrophy;C1848207:Poor speech;C5231391:Congenital cerebellar hypoplasia (1)

Cerebellar ataxia;C0011849:Diabetes mellitus;C0026850:Muscular dystrophy;C5231391:Congenital cerebellar hypoplasia (1)

Congenital cerebellar hypoplasia (1)

Congenital disorder of glycosylation (1)

Congenital disorder of glycosylation type I (1)

Focal segmental glomerulosclerosis (1)

Inborn genetic diseases (1)

PMM2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.94

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

1.0

MetaRNN

Benign

0.021

MetaSVM

Uncertain

0.76

MutationAssessor

Pathogenic

4.1

PhyloP100

9.8

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-4.8

REVEL

Pathogenic

0.93

Sift

Benign

0.033

Sift4G

Uncertain

0.040

Polyphen

0.99

Vest4

0.89

MVP

0.98

MPC

0.041

ClinPred

0.13

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.88

gMVP

0.89

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over