12-102840477-C-G

Position:

• chr12-102840477-C-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM3 PP3 PP4_Moderate PM2 PS3

This summary comes from the ClinGen Evidence Repository: PAH-specific ACMG/AMP criteria applied: PS3: In vitro expression of altered protein in COS cells produces severe decrease of PAH activity (<3%); PM2: Extremely low frequency. ExAC MAF=0.00012; PP4_Moderate: Detected in PKU patients, BH4 deficiency excluded; PP3: Predicted deleterious in SIFT, Polyphen-2, MutationTaster. REVEL=0.895; PM3: Detected with V388M (pathogenic) in 2 patients (PMID:9860305; PMID:21307867). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PS3, PM2, PP4_Moderate, PP3, PM3). LINK:https://erepo.genome.network/evrepo/ui/classification/CA229414/MONDO:0009861/006

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:10 O:1
• Conservation: PhyloP100: 0.933

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 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/exons	MANE	Protein	UniProt
PAH	NM_000277.3	c.1238G>C	p.Arg413Pro	missense_variant	12/13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.1238G>C	p.Arg413Pro	missense_variant	13/14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.1238G>C	p.Arg413Pro	missense_variant	12/13	1	NM_000277.3	ENSP00000448059.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251440 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135892

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000157 AC: 23 AN: 1461692 Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12 AN XY: 727154

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000302

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:7

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 1991	- -
Pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Aug 05, 2018	PAH-specific ACMG/AMP criteria applied: PS3: In vitro expression of altered protein in COS cells produces severe decrease of PAH activity (<3%); PM2: Extremely low frequency. ExAC MAF=0.00012; PP4_Moderate: Detected in PKU patients, BH4 deficiency excluded; PP3: Predicted deleterious in SIFT, Polyphen-2, MutationTaster. REVEL=0.895; PM3: Detected with V388M (pathogenic) in 2 patients (PMID:9860305; PMID:21307867). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PS3, PM2, PP4_Moderate, PP3, PM3). -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 08, 2024	This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 413 of the PAH protein (p.Arg413Pro). This variant is present in population databases (rs79931499, gnomAD 0.006%). This missense change has been observed in individual(s) with PAH-related disease (PMID: 24401910, 27264808). ClinVar contains an entry for this variant (Variation ID: 592). 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%. Experimental studies have shown that this missense change affects PAH function (PMID: 17935162, 21953985). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 05, 2016	Variant summary: The PAH c.1238G>C (p.Arg413Pro) variant causes a missense change involving a non-conserved nucleotide with 5/5 in silico tools predicting a damaging outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency 1/121344, which does not exceed the estimated maximal expected allele frequency for a pathogenic PAH variant of 1/126. The variant of interest was found in multiple affected individuals diagnosed with classic PKU via publications and has been indicated that it is predominantly observed in populations of Asian origin. In addition, publications indicated that the patients showed zero PAH activity. In addition, multiple databases/clinical laboratories cite the variant as "pathogenic." Therefore, the variant of interest has been classified as "pathogenic." -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	May 04, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 26, 2024	- -

not provided Pathogenic:3 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 01, 2023	PP3, PM2_moderate, PM3, PS3 -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 07, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 28, 2023	Functional studies found this variant is associated with severely diminished or completely absent of PAH enzyme activity compared to wildtype, supporting a damaging effect (Himmelreich et al., 2018; Wang et al., 1991); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Classified as responsive to tetrahydrobiopterin (BH4) therapy (Zurfluh et al. 2008); This variant is associated with the following publications: (PMID: 14654665, 8051931, 27173423, 29413232, 34704413, 29499199, 24401910, 21953985, 1301187, 2006152, 27264808, 25750018, 8929956, 25550961, 10484807, 9048935, 29317692, 30221392, 31355225, 30747360, 30275481, 26322415, 21307867, 15319459, 9860305, 1998345, 33677757, 32668217, 32778825, 30037505, 35314707, 29353259, 35405047, 33161754, 17935162, 16253218) -
not provided, no classification provided	literature only	DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.48
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.99	D;D
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.1	H;.
PrimateAI	Benign	0.24	T
PROVEAN	Pathogenic	-5.7	D;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.023	D;D
Polyphen		0.88	P;.
Vest4		0.94
MutPred		0.95		Loss of methylation at R413 (P = 0.0508);.;
MVP		0.94
MPC		0.26
ClinPred		0.99	D
GERP RS		-1.6
Varity_R		0.96
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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

Other links and lift over

dbSNP: rs79931499; hg19: chr12-103234255;