12-102852858-G-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP4PP3PM3PS3

This summary comes from the ClinGen Evidence Repository: The c.799C>G (p.Gln267Glu) variant in PAH was reported in 2 Chinese PKU patients. BH4 deficiencies not completely ruled out. (PMID:26600521) This variant was detected with known pathogenic variants p.R111X (PMID:16256386), and D101N (not in ClinVar, PMID:26600521). It is absent from ExAC, gnomAD, 1000G, and ESP. This variant is predicted deleterious in SIFT, Polyphen2, MutationTaster, and REVEL=0.935. This variant was expressed in e. coli using a rat Q267E mutant. It has 11% activity of wt. based on duplicate determinations of a single clone. (PMID:7914195). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PS3, PP3, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229769/MONDO:0009861/006

Frequency

Genomes: not found (cov: 32)

Consequence

PAH
NM_000277.3 missense

Scores

14
4
1

Clinical Significance

Pathogenic reviewed by expert panel P:1O:1

Conservation

PhyloP100: 10.0
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PS3
For more information check the summary or visit ClinGen Evidence Repository.
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 rank MANE Protein UniProt
PAHNM_000277.3 linkc.799C>G p.Gln267Glu missense_variant Exon 7 of 13 ENST00000553106.6 NP_000268.1 P00439A0A024RBG4
PAHNM_001354304.2 linkc.799C>G p.Gln267Glu missense_variant Exon 8 of 14 NP_001341233.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PAHENST00000553106.6 linkc.799C>G p.Gln267Glu missense_variant Exon 7 of 13 1 NM_000277.3 ENSP00000448059.1 P00439
PAHENST00000307000.7 linkc.784C>G p.Gln262Glu missense_variant Exon 8 of 14 5 ENSP00000303500.2 J3KND8
PAHENST00000549247.6 linkn.558C>G non_coding_transcript_exon_variant Exon 1 of 6 2
PAHENST00000635477.1 linkc.-42C>G upstream_gene_variant 5 ENSP00000489230.1 A0A0U1RQY4

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1Other:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Phenylketonuria Pathogenic:1
Dec 10, 2018
ClinGen PAH Variant Curation Expert Panel
Significance: Pathogenic
Review Status: reviewed by expert panel
Collection Method: curation

The c.799C>G (p.Gln267Glu) variant in PAH was reported in 2 Chinese PKU patients. BH4 deficiencies not completely ruled out. (PMID: 26600521) This variant was detected with known pathogenic variants p.R111X (PMID: 16256386), and D101N (not in ClinVar, PMID: 26600521). It is absent from ExAC, gnomAD, 1000G, and ESP. This variant is predicted deleterious in SIFT, Polyphen2, MutationTaster, and REVEL=0.935. This variant was expressed in e. coli using a rat Q267E mutant. It has 11% activity of wt. based on duplicate determinations of a single clone. (PMID: 7914195). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PS3, PP3, PP4. -

not provided Other:1
-
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.52
BayesDel_addAF
Pathogenic
0.58
D
BayesDel_noAF
Pathogenic
0.60
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
1.0
D;D
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
1.0
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
D;D
M_CAP
Pathogenic
0.59
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Pathogenic
0.95
D
MutationAssessor
Pathogenic
4.1
H;.
PrimateAI
Uncertain
0.76
T
PROVEAN
Uncertain
-2.9
D;D
REVEL
Pathogenic
0.94
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0010
D;D
Polyphen
1.0
D;.
Vest4
0.90
MutPred
0.94
Gain of catalytic residue at Q267 (P = 0.0635);.;
MVP
0.99
MPC
0.25
ClinPred
1.0
D
GERP RS
5.7
Varity_R
0.97
gMVP
0.99

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.

Other links and lift over

dbSNP: rs199475676; hg19: chr12-103246636; API