12-102843701-A-G

Position:

• chr12-102843701-A-G

Variant summary

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

This summary comes from the ClinGen Evidence Repository: The c.1144T>C (p.Phe382Leu) variant in PAH has been reported in 1 homozygous individual with mild HPA and BH4 deficiency excluded (PP4_Moderate; 0.5 points; PMID:21147011) and has also been reported in a patient from southern Italy (PMID:17096675; PMID:18346471) with mild hyperphenylalanemia (serum Phe 182 umol/L; not specified if BH4 deficiency excluded), who harbored it in presumed trans with the p.R252W variant (Pathogenic in ClinVar by 10 submitters, variation ID 584) (0.5 points) (PM3, 1 point total). This variant was absent in population databases (PM2). Expressed in COS-1 cells, this variant has 18% enzyme activity (PS3; PMID:22698810). Computational prediction tools suggest that the variant may impact the protein (REVEL = 0.89; PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PS3, PM2, PM3, PP4_moderate, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA386493225/MONDO:0009861/006

• Frequency: Genomes: not found (cov: 31)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:2 U:1
• Conservation: PhyloP100: 9.32

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAH	NM_000277.3	c.1144T>C	p.Phe382Leu	missense_variant	11/13	ENST00000553106.6
PAH	NM_001354304.2	c.1144T>C	p.Phe382Leu	missense_variant	12/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAH	ENST00000553106.6	c.1144T>C	p.Phe382Leu	missense_variant	11/13	1	NM_000277.3	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:2 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Feb 28, 2018	- -
Pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Feb 13, 2021	The c.1144T>C (p.Phe382Leu) variant in PAH has been reported in 1 homozygous individual with mild HPA and BH4 deficiency excluded (PP4_Moderate; 0.5 points; PMID: 21147011) and has also been reported in a patient from southern Italy (PMID: 17096675; PMID: 18346471) with mild hyperphenylalanemia (serum Phe 182 umol/L; not specified if BH4 deficiency excluded), who harbored it in presumed trans with the p.R252W variant (Pathogenic in ClinVar by 10 submitters, variation ID 584) (0.5 points) (PM3, 1 point total). This variant was absent in population databases (PM2). Expressed in COS-1 cells, this variant has 18% enzyme activity (PS3; PMID: 22698810). Computational prediction tools suggest that the variant may impact the protein (REVEL = 0.89; PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PS3, PM2, PM3, PP4_moderate, PP3. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 24, 2021	This variant is not present in population databases (gnomAD no frequency). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 382 of the PAH protein (p.Phe382Leu). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 21147011). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Studies have shown that this missense change results in skipping of exon 11 and introduces a premature termination codon (PMID: 22698810). The resulting mRNA is expected to undergo nonsense-mediated decay. Experimental studies have shown that this missense change affects PAH function (PMID: 22698810). 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. ClinVar contains an entry for this variant (Variation ID: 556882). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;D
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.8	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-4.0	D;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		0.71	P;.
Vest4		0.86
MutPred		0.92		Loss of sheet (P = 0.0817);.;
MVP		0.97
MPC		0.057
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.70
gMVP		0.91

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

Other links and lift over

dbSNP: rs1555203681; hg19: chr12-103237479;