4-17487231-A-G

Variant names:

• chr4-17487231-A-G
• rs777797545
• NM_000320.3:c.635T>C

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_000320.3(QDPR):​c.635T>C​(p.Phe212Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,494 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. F212Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: QDPR NM_000320.3 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 8.03
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• dihydropteridine reductase deficiency

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

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 24 curated pathogenic missense variants (we use a threshold of 10). The gene has 7 curated benign missense variants. Gene score misZ: 0.28456 (below the threshold of 3.09). Trascript score misZ: 0.32173 (below the threshold of 3.09). GenCC associations: The gene is linked to dihydropteridine reductase deficiency.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.922
• PP5: Variant 4-17487231-A-G is Pathogenic according to our data. Variant chr4-17487231-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2775915.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	c.635T>C	p.Phe212Ser	missense_variant	Exon 7 of 7	ENST00000281243.10	NP_000311.2
QDPR	NM_001306140.2	c.542T>C	p.Phe181Ser	missense_variant	Exon 6 of 6		NP_001293069.1
QDPR	NR_156494.2	n.562T>C		non_coding_transcript_exon_variant	Exon 6 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
QDPR	ENST00000281243.10	c.635T>C	p.Phe212Ser	missense_variant	Exon 7 of 7	1	NM_000320.3	ENSP00000281243.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461494 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727072

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111656

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dihydropteridine reductase deficiency Pathogenic:2

Apr 30, 2025

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: QDPR c.635T>C (p.Phe212Ser) results in a non-conservative amino acid change 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 250950 control chromosomes. c.635T>C has been observed in homozygous or compound heterozygous genotype in individuals affected with Dihydropteridine Reductase Deficiency (Loureno_2021, Ray_2022). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in lack of enzymatic activity (Loureno_2021). The following publications have been ascertained in the context of this evaluation (PMID: 34485013, 34997870). ClinVar contains an entry for this variant (Variation ID: 2775915). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Dec 04, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely 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 212 of the QDPR protein (p.Phe212Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with dihydropteridine reductase deficiency (PMID: 34485013, 34997870). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. 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. This variant disrupts the p.Phe212 amino acid residue in QDPR. Other variant(s) that disrupt this residue have been observed in individuals with QDPR-related conditions (PMID: 1283784), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.64	T;T
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.5	M;.
PhyloP100		8.0
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-6.4	D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;.
Vest4		0.79
MutPred		0.67		Gain of disorder (P = 0.0274);.;
MVP		0.96
MPC		0.94
ClinPred		0.99	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		0.90
Mutation Taster		=11/89	disease causing

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: rs777797545; hg19: chr4-17488854;