rs62514952

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000277.3(PAH):c.814G>T(p.Gly272Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000527 in 1,613,926 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. G272G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000052 ( 0 hom. )

Consequence

PAH
NM_000277.3 stop_gained

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:16O:1

Conservation

PhyloP100: 0.394

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 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 12-102852843-C-A is Pathogenic according to our data. Variant chr12-102852843-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 596.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr12-102852843-C-A is described in Lovd as [Pathogenic]. Variant chr12-102852843-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAH	NM_000277.3 linkuse as main transcript	c.814G>T	p.Gly272Ter	stop_gained	7/13	ENST00000553106.6
PAH	NM_001354304.2 linkuse as main transcript	c.814G>T	p.Gly272Ter	stop_gained	8/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
PAH	ENST00000553106.6 linkuse as main transcript	c.814G>T	p.Gly272Ter	stop_gained	7/13	1	NM_000277.3	P1
PAH	ENST00000307000.7 linkuse as main transcript	c.799G>T	p.Gly267Ter	stop_gained	8/14	5
PAH	ENST00000549247.6 linkuse as main transcript	n.573G>T		non_coding_transcript_exon_variant	1/6	2
PAH	ENST00000635477.1 linkuse as main transcript			upstream_gene_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000358

AC:

AN:

251358

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135838

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:

0.0000704

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000520

AC:

AN:

1461830

Hom.:

Cov.:

AF XY:

0.0000495

AC XY:

AN XY:

727216

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:

0.0000674

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000592

AC:

AN:

152096

Hom.:

Cov.:

AF XY:

0.0000808

AC XY:

AN XY:

74294

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000978

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 31, 2018	Variant summary: PAH c.814G>T (p.Gly272X) 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. The variant allele was found at a frequency of 5.1e-05 in 277088 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (5.1e-05 vs 0.0079), allowing no conclusion about variant significance. c.814G>T has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria)(Jeannesson-Thivisol_2015, Aldamiz-Echevarria_2016). These data indicate that the variant is very likely to be associated with disease. The variant was found to cause a loss of enzyme activity via functional studies (Aldamiz-Echevarria_2016). Three ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 1993	- -
Pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Aug 10, 2018	PAH-specific ACMG/AMP criteria applied: PM2: Absent from 1000G, ESP. Extrememly low frequency in ExAC, gnomAD (MAF= 0.00006, 0.0003093); PVS1: Nonsense variant. Predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay.; PP4: G272X found on one allele of a patient with classic PKU (PMID:1975559). 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: (PM2, PVS1, PP4). -
Pathogenic, criteria provided, single submitter	research	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	-	The PAH c.814G>T (p.G272*) nonsense variant is predicted to result in premature termination of the PAH protein and/or nonsense-mediated decay. This variant has been previously reported as pathogenic in individuals with phenylketonuria (PMID: 8370573; 1975559; 1978553; 17935162; 10471838; 12655550). -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 25, 2023	This sequence change creates a premature translational stop signal (p.Gly272*) 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 (rs62514952, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with PKU (PMID: 1975559, 10471838). ClinVar contains an entry for this variant (Variation ID: 596). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 18, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 28, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 09, 2019	NM_000277.1(PAH):c.814G>T(G272) is classified as pathogenic in the context of phenylalanine hydroxylase deficiency and is associated with the classic form of disease. Sources cited for classification include the following: PMID 1671881, 24350308, 1978553, 10471838, 1975559 and 12655550. Classification of NM_000277.1(PAH):c.814G>T(G272) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -

not provided

Pathogenic:6Other:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 02, 2021	Reported in multiple patients with classic PKU, and one patient with mild PKU, in the presence of a second variant; also reported in a patient with classic PKU in the homozygous state (Svensson et al., 1990; Jeannesson-Thivisol et al., 2015; Williams et al., 2015); Associated with approximately 6%-7% residual activity compared to wild-type (Ho et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Classified as not responsive to BH4 therapy (Zurfluh et al. 2008); This variant is associated with the following publications: (PMID: 8444221, 10471838, 17935162, 22975760, 25525159, 23532445, 1975559, 25551302, 8889583, 29555771, 29431110, 31980526, 32668217, 33101986, 8188310, 32853555, 31589614, 26666653, 33375644, 27535533) -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 15, 2018	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
not provided, no classification provided	literature only	DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Oct 05, 2020	- -

PAH-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 13, 2024

The PAH c.814G>T variant is predicted to result in premature protein termination (p.Gly272*). This variant has been reported in the homozygous state or with a second pathogenic PAH variant in many patients with phenylalanine hydroxylase deficiency (for example, see Table S3 in Hillert A et al 2020. PubMed ID: 32668217). This variant and has been reported to essentially abolish PAH enzyme activity, and patients with this variant have been reported to be non-responsive to tetrahydrobiopterin (BH4) (Zurflüh et al. 2008. PubMed ID: 17935162). (Zurflüh et al. 2008. PubMed ID: 17935162). In the homozygous state, the c.814G>T variant has been associated with classical phenylketonuria (PKU) (Ellingsen et al. 1999. PubMed ID: 10471838). The ClinGen PAH Curation Expert Panel and multiple other outside laboratories classify this variant as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/596/). Nonsense variants in PAH are expected to be pathogenic. Based on these observations, we also interpret this variant as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.60

Cadd

Pathogenic

Dann

Uncertain

0.99

Eigen

Pathogenic

0.73

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Benign

0.39

MutationTaster

Benign

1.0

A;A

Vest4

0.80

GERP RS

5.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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