chr12-102844370-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM3_StrongPP3PM2PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The c.1031G>A (p.Gly344Asp) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded, PMID:26503515). This variant is absent in population databases. This variant was detected in with multiple pathogenic variants: p.Arg241Cys (PMID:18985011); p.R252Q (PMID:26322415); EX6-96A>G (PMID:29316886); p.Q232* (PMID:30050108). Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PP4_Moderate, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229288/MONDO:0009861/006

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

17
1
1

Clinical Significance

Likely pathogenic reviewed by expert panel P:4O:1

Conservation

PhyloP100: 7.91
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 Likely_pathogenic. Variant got 9 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 linkc.1031G>A p.Gly344Asp missense_variant 10/13 ENST00000553106.6 NP_000268.1 P00439A0A024RBG4
PAHNM_001354304.2 linkc.1031G>A p.Gly344Asp missense_variant 11/14 NP_001341233.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PAHENST00000553106.6 linkc.1031G>A p.Gly344Asp missense_variant 10/131 NM_000277.3 ENSP00000448059.1 P00439

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461474
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
727068
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:4Other:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Phenylketonuria Pathogenic:4
Likely pathogenic, reviewed by expert panelcurationClinGen PAH Variant Curation Expert PanelJun 11, 2021The c.1031G>A (p.Gly344Asp) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded, PMID: 26503515). This variant is absent in population databases. This variant was detected in with multiple pathogenic variants: p.Arg241Cys (PMID: 18985011); p.R252Q (PMID: 26322415); EX6-96A>G (PMID: 29316886); p.Q232* (PMID: 30050108). Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PP4_Moderate, PP3. -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsMay 30, 2022- -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 10, 2024This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 344 of the PAH protein (p.Gly344Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with phenylketonuria (PMID: 18985011, 26322415). ClinVar contains an entry for this variant (Variation ID: 102481). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PAH protein function with a positive predictive value of 80%. This variant disrupts the p.Gly344 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17502162, 26600521, 32668217). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMay 21, 2024Variant summary: PAH c.1031G>A (p.Gly344Asp) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain (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 251240 control chromosomes. c.1031G>A has been reported in the literature in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (Hillert_2020, Li_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32668217, 30050108). ClinVar contains an entry for this variant (Variation ID: 102481). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
not provided Other:1
not provided, no classification providedliterature onlyDeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
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
1.1
Eigen_PC
Pathogenic
1.0
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
D;D
M_CAP
Pathogenic
0.83
D
MetaRNN
Pathogenic
1.0
D;D
MetaSVM
Pathogenic
0.97
D
MutationAssessor
Pathogenic
4.5
H;.
PrimateAI
Pathogenic
0.88
D
PROVEAN
Pathogenic
-6.8
D;D
REVEL
Pathogenic
0.99
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;.
Vest4
0.96
MutPred
0.99
Loss of sheet (P = 0.0817);.;
MVP
0.99
MPC
0.26
ClinPred
1.0
D
GERP RS
5.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.98
gMVP
1.0

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: rs62508582; hg19: chr12-103238148; COSMIC: COSV105126805; API