rs751203209

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PP3PP4PM2PM3_Supporting

This summary comes from the ClinGen Evidence Repository: The c.870T>G (p.His290Gln) variant in PAH has been reported in one patient with classic PKU (BH4 deficiency not excluded; PP4; PMID:26210745). It was detected with known pathogenic variant p.R261Q, but parental testing was not reported/performed. This variant is absent from 1000G, ESP, ExAC and gnomAD. A deleterious effect is predicted in SIFT, Polyphen-2, MutationTaster, and REVEL=0.924. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PP3, PM3_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16020878/MONDO:0009861/006

Frequency

Genomes: not found (cov: 32)

Consequence

PAH
NM_000277.3 missense

Scores

12
5
2

Clinical Significance

Likely pathogenic reviewed by expert panel P:1U:1

Conservation

PhyloP100: 0.0870
Variant links:
Genes affected
PAH (HGNC:8582): (phenylalanine hydroxylase) This gene encodes a member of the biopterin-dependent aromatic amino acid hydroxylase protein family. The encoded phenylalanine hydroxylase enzyme hydroxylates phenylalanine to tyrosine and is the rate-limiting step in phenylalanine catabolism. Deficiency of this enzyme activity results in the autosomal recessive disorder phenylketonuria. [provided by RefSeq, Aug 2017]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2
For more information check the summary or visit ClinGen Evidence Repository.
PM3
For more information check the summary or visit ClinGen Evidence Repository.
PP3
For more information check the summary or visit ClinGen Evidence Repository.
PP4
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PAHNM_000277.3 linkuse as main transcriptc.870T>G p.His290Gln missense_variant 8/13 ENST00000553106.6 NP_000268.1 P00439A0A024RBG4
PAHNM_001354304.2 linkuse as main transcriptc.870T>G p.His290Gln missense_variant 9/14 NP_001341233.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PAHENST00000553106.6 linkuse as main transcriptc.870T>G p.His290Gln missense_variant 8/131 NM_000277.3 ENSP00000448059.1 P00439

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1Uncertain:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Phenylketonuria Pathogenic:1Uncertain:1
Likely pathogenic, reviewed by expert panelcurationClinGen PAH Variant Curation Expert PanelDec 12, 2021The c.870T>G (p.His290Gln) variant in PAH has been reported in one patient with classic PKU (BH4 deficiency not excluded; PP4; PMID: 26210745). It was detected with known pathogenic variant p.R261Q, but parental testing was not reported/performed. Functional studies show low but measurable activities for tyrosine formation and greatly decreased the affinity for iron (PMID: 18477464). This variant is absent from 1000G, ESP, ExAC and gnomAD. A deleterious effect is predicted in SIFT, Polyphen-2, MutationTaster, and REVEL=0.924. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PP3, PM3_supporting, PS3_supporting. -
Uncertain significance, criteria provided, single submitterclinical testingCounsylMay 31, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.51
D
BayesDel_noAF
Pathogenic
0.50
CADD
Benign
16
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
1.0
D;D
Eigen
Uncertain
0.20
Eigen_PC
Benign
-0.036
FATHMM_MKL
Uncertain
0.79
D
LIST_S2
Pathogenic
0.98
D;D
M_CAP
Pathogenic
0.86
D
MetaRNN
Pathogenic
1.0
D;D
MetaSVM
Uncertain
0.77
D
MutationAssessor
Pathogenic
4.9
H;.
PrimateAI
Uncertain
0.74
T
PROVEAN
Pathogenic
-7.8
D;D
REVEL
Pathogenic
0.92
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0010
D;D
Polyphen
1.0
D;.
Vest4
0.96
MutPred
0.98
Gain of loop (P = 0.2045);.;
MVP
0.97
MPC
0.24
ClinPred
1.0
D
GERP RS
-4.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.99
gMVP
0.99

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
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.

Other links and lift over

dbSNP: rs751203209; hg19: chr12-103245507; API