rs104894489

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_002435.3(MPI):c.656G>A(p.Arg219Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000268 in 1,614,086 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00028 ( 0 hom. )

Consequence

MPI
NM_002435.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 9.62

Variant links:

Genes affected

MPI (HGNC:7216): (mannose phosphate isomerase) Phosphomannose isomerase catalyzes the interconversion of fructose-6-phosphate and mannose-6-phosphate and plays a critical role in maintaining the supply of D-mannose derivatives, which are required for most glycosylation reactions. Mutations in the MPI gene were found in patients with carbohydrate-deficient glycoprotein syndrome, type Ib. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

MPI links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 15-74893306-G-A is Pathogenic according to our data. Variant chr15-74893306-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 14345.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-74893306-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MPI	NM_002435.3 link	c.656G>A	p.Arg219Gln	missense_variant	Exon 5 of 8	ENST00000352410.9	NP_002426.1	P34949-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MPI	ENST00000352410.9 link	c.656G>A	p.Arg219Gln	missense_variant	Exon 5 of 8	1	NM_002435.3	ENSP00000318318.6		P34949-1

Frequencies

GnomAD3 genomes

AF:

0.000197

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000753

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000291

AC:

AN:

250746

Hom.:

AF XY:

0.000295

AC XY:

AN XY:

135612

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000231

Gnomad NFE exome

AF:

0.000540

Gnomad OTH exome

AF:

0.000978

GnomAD4 exome

AF:

0.000276

AC:

403

AN:

1461870

Hom.:

Cov.:

AF XY:

0.000270

AC XY:

196

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000449

Gnomad4 NFE exome

AF:

0.000314

Gnomad4 OTH exome

AF:

0.000381

GnomAD4 genome

AF:

0.000197

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000753

Gnomad4 NFE

AF:

0.000265

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000194

Hom.:

Bravo

AF:

0.000113

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000453

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

MPI-congenital disorder of glycosylation

Pathogenic:6

Jun 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 219 of the MPI protein (p.Arg219Gln). This variant is present in population databases (rs104894489, gnomAD 0.05%). This missense change has been observed in individual(s) with CDG type Ib (PMID: 10980531, 11350186, 18928705). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14345). 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 not expected to disrupt MPI protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects MPI function (PMID: 9525984, 24421398). For these reasons, this variant has been classified as Pathogenic. -

Jul 14, 2016

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MPI c.656G>A (p.Arg219Gln) missense variant has been reported in five studies in which it is found in a total of six individuals with MPI- congenital disorders of glycosylation (CDG-Ib), including one homozygote and five compound heterozygotes (Niehues et al. 1998; Schollen et al. 2000; Westphal et al. 2001; MartÃn HernÃ¡ndez et al. 2008; Helander et al. 2014). The variant was also identified in a homozygous state in an individual who showed elevated carbohydrate-deficient transferrin levels but no other clinical signs of MPI-CDG (CDG-Ib), and in a heterozygous state in three unaffected parents of patients. The variant was absent from 50 controls but is reported at a frequency of 0.00078 in the European (non-Finnish) population of the Exome Aggregation Consortium. Expression studies in COS-7 cells showed that the variant protein resulted in MPI activity indistinguishable from background, while expression of normal MPI increased specific activity approximately 10 fold when compared with controls (Niehues et al. 1998). Based on the collective evidence, the p.Arg219Gln 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. -

Mar 27, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 26, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided

Pathogenic:2

Apr 21, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect, specifically, R219Q is associated with significantly reduced mannose-6-phosphate isomerase activity compared to wild-type (Niehues et al., 1998); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 24508628, 10980531, 26206375, 9525984, 18928705, 28928705, 24421398, 30545931, 11350186, 33204592, 31589614, 33643843, 33413482) -

Aug 09, 2021

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the MPI gene demonstrated two sequence changes. The first sequence change, c.656G>A, in exon 5, results in an amino acid change, p.Arg219Gln. This sequence change has been described in gnomAD with a low population frequency of 0.029% (dbSNP rs104894489). The p.Arg219Gln change affects a highly conserved amino acid residue located in a domain of the MPI protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg219Gln substitution. This sequence change has been reported in the homozygous and compound heterozygous states in multiple individuals with features of congenital disorder of glycosylation (PMIDs: 10980531, 18928705, 11350186, 9525984). Functional studies have also demonstrated that the p.Arg219Gln change affects MPI protein function (PMID: 9525984, 24421398). Based on the collective evidence, the p.Arg219Gln variant is classified as pathogenic for congenital disorders of glycosylation -

MPI-related disorder

Pathogenic:1

Jul 03, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MPI c.656G>A variant is predicted to result in the amino acid substitution p.Arg219Gln. This variant has been reported, along with a second known or plausible causative variant, in individuals with autosomal recessive congenital disorder of glycosylation 1b (see, for example, Schollen et al. 2000. PubMed ID: 10980531; Niehues et al. 1998. PubMed ID: 9525984; Abdel Ghaffar et al. 2020. PubMed ID: 33204592; Westphal et al. 2001. PubMed ID: 11350186; Starosta et al. 2021. PubMed ID: 33413482; Lipinski et al. 2021. PubMed ID: 33643843; de la Morena-Barrio et al. 2019. PubMed ID: 30545931). This variant has also been reported in the homozygous state in two siblings with a highly elevated serum level of carbohydrate-deficient transferrin, a biomarker for MPI-related disease, but were otherwise clinically asymptomatic (Helander et al. 2014. PubMed ID: 24508628). This variant is reported in 0.050% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Based on the available evidence, we classify this variant as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.83

D;D;D;D;.;D;D;.

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D;D;D;D;D;D;D

M_CAP

Uncertain

0.24

MetaRNN

Uncertain

0.73

D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.8

.;M;.;.;.;.;.;.

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-3.0

D;D;D;D;D;D;D;D

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0060

D;D;D;D;D;D;D;T

Sift4G

Benign

0.076

T;D;T;D;D;D;D;T

Polyphen

0.99

.;D;.;.;.;.;.;.

Vest4

0.91, 0.87, 0.88, 0.94, 0.90, 0.87, 0.69

MVP

0.94

MPC

0.77

ClinPred

0.50

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.80

gMVP

0.84

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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