Variant chr12-102844345-AC-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP4

This summary comes from the ClinGen Evidence Repository: PAH-specific ACMG/AMP criteria applied: PVS1: Frameshift variant; PM2: Extremely low frequency in ExAC, MAF=0.00002.; PP4: Identified in a pair of siblings with PKU. (PMID:7913581). 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: (PVS1, PM2, PP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA229311/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

PAH
ENST00000553106.6 frameshift

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:12O:1

Conservation

PhyloP100: 7.91

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 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.

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 linkuse as main transcript	c.1055del	p.Gly352ValfsTer48	frameshift_variant	10/13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2 linkuse as main transcript	c.1055del	p.Gly352ValfsTer48	frameshift_variant	11/14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6 linkuse as main transcript	c.1055del	p.Gly352ValfsTer48	frameshift_variant	10/13	1	NM_000277.3	ENSP00000448059	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152174

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251200

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135762

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:

0.0000144

AC:

AN:

1458210

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

725610

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:

0.0000144

Gnomad4 OTH exome

AF:

0.0000829

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74340

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:9

Pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Aug 10, 2018	PAH-specific ACMG/AMP criteria applied: PVS1: Frameshift variant; PM2: Extremely low frequency in ExAC, MAF=0.00002.; PP4: Identified in a pair of siblings with PKU. (PMID:7913581). 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: (PVS1, PM2, PP4). -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 21, 2017	Variant summary: The c.1055delG (p.Gly352Valfs) variant in PAH gene is a frameshift change that results in the loss of ~162 amino acids of the PAH protein (~11%). This change is predicted to cause loss of normal protein function through protein truncation or nonsense-mediated mRNA decay. The variant is present at a low frequency in the large control population datasets of ExAC (8.351e-06; 1/119744 chrs tested). The c.1055delG has been reported in multiple affected individuals with biochemically confirmed PKU via published reports. This variant is associated with predominantly severe clinical phenotype and homozygous patients are non-responsive to BH4 therapy. Lastly, it is cited as Pathogenic by reputable databases/clinical laboratories. Taking together, the variant was classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 27, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 14, 2018	The PAH c.1055delG (p.Gly352ValfsTer48) variant is predicted to result in a frameshift and premature truncation of the protein. Across a selection of the available literature, the p.Gly352ValfsTer48 variant has been reported in at least 37 unrelated individuals with phenylalanine hydroxylase deficiency, including in a homozygous state in 21 individuals, in a compound heterozygous state in 15 individuals, and in a heterozygous state in one individual in whom a second variant was not identified (Rozen et al. 1994; Daniele et al. 2009; Dahri et al. 2010; Jeannesson-Thivisol et al. 2015). Most of these cases showed a classic phenotype; 14 individuals who were severely affected displayed clinical symptoms due to delayed diagnosis and treatment. Control data are unavailable for the p.Gly352ValfsTer48 variant, which is reported at a frequency of 0.000015 in the European (non-Finnish) population of the Exome Aggregation Consortium. This frequency is based on one allele only in a region of good sequence coverage, suggesting the variant is rare. Based on the collective evidence, the p.Gly352ValfsTer48 variant is classified as pathogenic for phenylalanine hydroxylase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 06, 2023	This sequence change creates a premature translational stop signal (p.Gly352Valfs*48) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with phenylketonuria (PKU) (PMID: 7913581). ClinVar contains an entry for this variant (Variation ID: 102498). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Sep 22, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Nov 16, 2021	ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderate, PM3 very strong, PP1 supporting, PP4 supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Feb 01, 2017	- -

not provided

Pathogenic:3Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 25, 2016	- -
not provided, no classification provided	literature only	DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 29, 2023	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34828281, 1301187, 24939588, 7545869, 21228398, 7913581, 19786003, 9781015, 9634518, 8069318, 33375644, 29749107, 33465300, 30375370, 10394930, 30829006, 19292873, 23430918, 26666653, 32668217, 27535533) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 29, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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