rs62514928

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM3_StrongPVS1PP4_ModeratePM2

This summary comes from the ClinGen Evidence Repository: The c.612T>G (p.Tyr204Ter) variant in PAH is a null variant (nonsense variant) in exon 6 of 13 in a gene where LOF is a known mechanism of disease, leading to premature truncation and NMD (PVS1). It is present at extremely low frequency in ethnically diverse control databases, with gnomAD AF 0.00000398 (<0.002, the PAH-specific cutoff) (PM2). It has been reported as a heterozygous variant in at least four PKU cases, with known pathogenic variants in at least two cases (PM3_Strong): with a Sicilian PKU case with BH4 deficiency excluded (PMID:8268925) (PP4_Moderate); in a German PKU case (PMID:10394930); in one Spanish case with the pathogenic (per PAH VCEP) p.R176L variant (PMID:10234516); and in one family (2 affected siblings) and 2 additional mild PKU patients with the pathogenic (per PAH VCEP) p.R68S variant (PMID:23514811). It has also been reported Pathogenic by three labs in ClinVar (variation ID 102758). Classification: PathogenicSupporting criteria: PVS1, PM2; PM3_Strong; PP4_Moderate LINK:https://erepo.genome.network/evrepo/ui/classification/CA229654/MONDO:0009861/006

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

PAH
ENST00000553106.6 stop_gained

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:6O:1

Conservation

PhyloP100: -1.47

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1

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.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PAH	NM_000277.3 linkuse as main transcript	c.612T>G	p.Tyr204Ter	stop_gained	6/13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2 linkuse as main transcript	c.612T>G	p.Tyr204Ter	stop_gained	7/14		NP_001341233.1
PAH	XM_017019370.2 linkuse as main transcript	c.612T>G	p.Tyr204Ter	stop_gained	6/7		XP_016874859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
PAH	ENST00000553106.6 linkuse as main transcript	c.612T>G	p.Tyr204Ter	stop_gained	6/13	1	NM_000277.3	ENSP00000448059	P1
PAH	ENST00000549111.5 linkuse as main transcript	n.708T>G		non_coding_transcript_exon_variant	6/6	1
PAH	ENST00000307000.7 linkuse as main transcript	c.597T>G	p.Tyr199Ter	stop_gained	7/14	5		ENSP00000303500
PAH	ENST00000551988.5 linkuse as main transcript			downstream_gene_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251338

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135828

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461788

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727202

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:

0.0000126

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 22, 2021	- -
Pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	May 08, 2020	The c.612T>G (p.Tyr204Ter) variant in PAH is a null variant (nonsense variant) in exon 6 of 13 in a gene where LOF is a known mechanism of disease, leading to premature truncation and NMD (PVS1). It is present at extremely low frequency in ethnically diverse control databases, with gnomAD AF 0.00000398 (<0.002, the PAH-specific cutoff) (PM2). It has been reported as a heterozygous variant in at least four PKU cases, with known pathogenic variants in at least two cases (PM3_Strong): with a Sicilian PKU case with BH4 deficiency excluded (PMID: 8268925) (PP4_Moderate); in a German PKU case (PMID: 10394930); in one Spanish case with the pathogenic (per PAH VCEP) p.R176L variant (PMID: 10234516); and in one family (2 affected siblings) and 2 additional mild PKU patients with the pathogenic (per PAH VCEP) p.R68S variant (PMID: 23514811). It has also been reported Pathogenic by three labs in ClinVar (variation ID 102758). Classification: Pathogenic Supporting criteria: PVS1, PM2; PM3_Strong; PP4_Moderate -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 07, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 22, 2019	Variant summary: PAH c.612T>G (p.Tyr204X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251338 control chromosomes (gnomAD). c.612T>G has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria)(Aldamiz-Echevarria_2016, Sarkissian_2011). These data indicate that the variant is very likely to be associated with disease. Two ClinVar submissions (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 21, 2023	This sequence change creates a premature translational stop signal (p.Tyr204*) in the PAH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518). This variant is present in population databases (rs62514928, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with phenylketonuria and hyperphenylalaninemia (PMID: 8268925, 23764561, 27121329, 27264808). ClinVar contains an entry for this variant (Variation ID: 102758). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1Other:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 29, 2016	The Y204X variant in the PAH gene has been reported as a pathogenic variant in the PAH Consortium database. The Y204X nonsense variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Patients who are homozygous for Y204X are reported to have classic PKU and are not responsive to BH4 therapy (Guldberg et al., 1993; BIOPKU database). Therefore, we interpret Y204X to be a pathogenic variant. -
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

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Uncertain

0.050

CADD

Benign

DANN

Benign

0.96

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.12

MutationTaster

Benign

1.0

A;A

Vest4

0.82

GERP RS

-8.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over