4-17511987-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_000320.3(QDPR):c.68G>A(p.Gly23Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0000211 in 1,610,618 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. G23A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

QDPR
NM_000320.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 4.96

Variant links:

Genes affected

QDPR (HGNC:9752): (quinoid dihydropteridine reductase) This gene encodes the enzyme dihydropteridine reductase, which catalyzes the NADH-mediated reduction of quinonoid dihydrobiopterin. This enzyme is an essential component of the pterin-dependent aromatic amino acid hydroxylating systems. Mutations in this gene resulting in QDPR deficiency include aberrant splicing, amino acid substitutions, insertions, or premature terminations. Dihydropteridine reductase deficiency presents as atypical phenylketonuria due to insufficient production of biopterin, a cofactor for phenylalanine hydroxylase. [provided by RefSeq, Jul 2008]

QDPR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 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, 3 uncertain in NM_000320.3

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.951

PP5

Variant 4-17511987-C-T is Pathogenic according to our data. Variant chr4-17511987-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
QDPR	NM_000320.3 link	c.68G>A	p.Gly23Asp	missense_variant	Exon 1 of 7	ENST00000281243.10	NP_000311.2	P09417-1A0A140VKA9
QDPR	NM_001306140.2 link	c.68G>A	p.Gly23Asp	missense_variant	Exon 1 of 6		NP_001293069.1	P09417-2
QDPR	NR_156494.2 link	n.104G>A		non_coding_transcript_exon_variant	Exon 1 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
QDPR	ENST00000281243.10 link	c.68G>A	p.Gly23Asp	missense_variant	Exon 1 of 7	1	NM_000320.3	ENSP00000281243.5		P09417-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152004

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000219

AC:

AN:

1458614

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

725662

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000505

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000261

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152004

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74258

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000278

Hom.:

Bravo

AF:

0.0000302

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Dihydropteridine reductase deficiency

Pathogenic:4

Jun 21, 2023

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: QDPR c.68G>A (p.Gly23Asp) results in a non-conservative amino acid change to a highly conserved residue (HGMD) in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 236940 control chromosomes (gnomAD). c.68G>A has been reported in the literature in multiple homozygous individuals affected with Dihydropteridine Reductase Deficiency (Dianzani_1998, Farrigua_2007), and at least one compound heterozygous individual with another pathogenic variant. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding a severe reduction in enzymatic activity in vitro (Zhang_1996). The following publications have been ascertained in the context of this evaluation (PMID: 9744478, 17188538). One submitter has cited a clinical-significance assessment for this variant to ClinVar after 2014 and classified it as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

May 24, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 01, 1993

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Sep 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 23 of the QDPR protein (p.Gly23Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with biopterin-deficient hyperphenylalaninemia (PMID: 8326489, 8518287, 27246466). ClinVar contains an entry for this variant (Variation ID: 490). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects QDPR function (PMID: 8518287). For these reasons, this variant has been classified as Pathogenic. -

Hyperphenylalaninemia due to tetrahydrobiopterin deficiency

Pathogenic:1

Pediatrics, Sichuan Provincial Hospital For Women And Children

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

proband，female, 1 month old, preliminary screening 358umol/L, erythrocytic dihydroteredine reductase determination 0.84nmol/ (min.5mmdisc) decreased, 40 days confirmed DHPRD -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.48

T;D;.;.

Eigen

Pathogenic

0.73

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.95

.;D;D;D

M_CAP

Pathogenic

0.96

MetaRNN

Pathogenic

0.95

D;D;D;D

MetaSVM

Pathogenic

0.90

MutationAssessor

Pathogenic

3.6

.;H;H;.

PrimateAI

Pathogenic

0.95

PROVEAN

Pathogenic

-6.9

D;D;D;D

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

.;D;.;.

Vest4

0.82

MVP

0.99

MPC

0.85

ClinPred

1.0

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

1.0

gMVP

0.95

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