12-102855169-G-T

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_000277.3(PAH):​c.673C>A​(p.Pro225Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,210 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P225R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

PAH
NM_000277.3 missense

Scores

16
2
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5O:1

Conservation

PhyloP100: 10.0

Publications

5 publications found
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]
PAH Gene-Disease associations (from GenCC):
  • phenylketonuria
    Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Myriad Women’s Health
  • classic phenylketonuria
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • maternal phenylketonuria
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • mild hyperphenylalaninemia
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • mild phenylketonuria
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • tetrahydrobiopterin-responsive hyperphenylalaninemia/phenylketonuria
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 19 ACMG points.

PM1
In a hotspot region, there are 27 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_000277.3
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr12-102855168-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 932277.Status of the report is reviewed_by_expert_panel, 3 stars.
PP2
Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 440 curated pathogenic missense variants (we use a threshold of 10). The gene has 8 curated benign missense variants. Gene score misZ: -0.64755 (below the threshold of 3.09). Trascript score misZ: -0.0084567 (below the threshold of 3.09). GenCC associations: The gene is linked to phenylketonuria, tetrahydrobiopterin-responsive hyperphenylalaninemia/phenylketonuria, maternal phenylketonuria, classic phenylketonuria, mild phenylketonuria, mild hyperphenylalaninemia.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.994
PP5
Variant 12-102855169-G-T is Pathogenic according to our data. Variant chr12-102855169-G-T is described in CliVar as Pathogenic. Clinvar id is 102779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-102855169-G-T is described in CliVar as Pathogenic. Clinvar id is 102779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-102855169-G-T is described in CliVar as Pathogenic. Clinvar id is 102779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-102855169-G-T is described in CliVar as Pathogenic. Clinvar id is 102779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-102855169-G-T is described in CliVar as Pathogenic. Clinvar id is 102779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-102855169-G-T is described in CliVar as Pathogenic. Clinvar id is 102779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-102855169-G-T is described in CliVar as Pathogenic. Clinvar id is 102779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-102855169-G-T is described in CliVar as Pathogenic. Clinvar id is 102779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-102855169-G-T is described in CliVar as Pathogenic. Clinvar id is 102779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-102855169-G-T is described in CliVar as Pathogenic. Clinvar id is 102779.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
PAHNM_000277.3 linkc.673C>A p.Pro225Thr missense_variant Exon 6 of 13 ENST00000553106.6 NP_000268.1 P00439A0A024RBG4
PAHNM_001354304.2 linkc.673C>A p.Pro225Thr missense_variant Exon 7 of 14 NP_001341233.1
PAHXM_017019370.2 linkc.673C>A p.Pro225Thr missense_variant Exon 6 of 7 XP_016874859.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PAHENST00000553106.6 linkc.673C>A p.Pro225Thr missense_variant Exon 6 of 13 1 NM_000277.3 ENSP00000448059.1 P00439
PAHENST00000549111.5 linkn.769C>A non_coding_transcript_exon_variant Exon 6 of 6 1
PAHENST00000307000.7 linkc.658C>A p.Pro220Thr missense_variant Exon 7 of 14 5 ENSP00000303500.2 J3KND8
PAHENST00000551988.5 linkn.*110C>A downstream_gene_variant 3

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152210
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
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
Cov.:
34
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152210
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74372
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41444
American (AMR)
AF:
0.00
AC:
0
AN:
15288
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5202
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4826
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10618
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68038
Other (OTH)
AF:
0.00
AC:
0
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.575
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:5Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Phenylketonuria Pathogenic:5
Jan 03, 2022
3billion
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000102779, PMID:9391881, PS1_S). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000102780,VCV000932277, PMID:10394930,10527663,21307867, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.988, 3CNET: 0.997, PP3_P). A missense variant is a common mechanism associated with Classic phenylketonuria (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Feb 17, 2020
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Variant summary: PAH c.673C>A (p.Pro225Thr) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal (IPR019774) of 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 251338 control chromosomes. c.673C>A has been widely reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) in literature originating from 1997 (Kozak_1997) through the present (example, Kuznetcova_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Mar 05, 2018
Counsyl
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Feb 19, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 225 of the PAH protein (p.Pro225Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 18299955, 22330942, 23430547). ClinVar contains an entry for this variant (Variation ID: 102779). 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 expected to disrupt PAH protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Apr 08, 2021
Natera, Inc.
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

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
Pathogenic
0.91
BayesDel_addAF
Pathogenic
0.58
D
BayesDel_noAF
Pathogenic
0.60
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
1.0
D;D
Eigen
Pathogenic
1.2
Eigen_PC
Pathogenic
1.0
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
1.0
D;D
M_CAP
Pathogenic
0.65
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Pathogenic
0.90
D
MutationAssessor
Pathogenic
4.9
H;.
PhyloP100
10
PrimateAI
Uncertain
0.68
T
PROVEAN
Pathogenic
-7.7
D;D
REVEL
Pathogenic
0.99
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;.
Vest4
0.98
MutPred
0.98
Loss of disorder (P = 0.1487);.;
MVP
0.99
MPC
0.25
ClinPred
1.0
D
GERP RS
5.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.98
gMVP
0.99
Mutation Taster
=0/100
disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs199475589; hg19: chr12-103248947; API