rs1555203681

Variant names:

• chr12-102843701-A-G
• rs1555203681
• NM_000277.3:c.1144T>C

Variant summary

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

• 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
PAH	NM_000277.3	c.1144T>C	p.Phe382Leu	missense_variant	Exon 11 of 13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.1144T>C	p.Phe382Leu	missense_variant	Exon 12 of 14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.1144T>C	p.Phe382Leu	missense_variant	Exon 11 of 13	1	NM_000277.3	ENSP00000448059.1

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

Feb 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 21147011). ClinVar contains an entry for this variant (Variation ID: 556882). 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 not expected to disrupt PAH protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PAH function (PMID: 22698810). 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. For these reasons, this variant has been classified as Pathogenic. -

Feb 13, 2021

ClinGen PAH Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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. -

Feb 28, 2018

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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;.
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;