Variant 12-102912793-CAA-CA details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PVS1PP4

This summary comes from the ClinGen Evidence Repository: The c.165delT (p.F55Lfs*6) is a frameshift variant in exon 2 of 13 in PAH, predicted to undergo nonsense mediated decay with the truncated region critical to protein function. It has been reported in compound heterozygote state in multiple patients with PKU (BH4 deficiency not excluded) (PMID:1682235 & 23500595). The variants in trans include: R408W, and R261Q, both confirmed pathogenic.This variant has an extremely low allele frequency in the Genome Aggregation database (3/251384) (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria: PM2, PP4, PVS1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA251540/MONDO:0009861/006

Frequency

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

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

PAH
ENST00000553106.6 frameshift

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:11O:1

Conservation

PhyloP100: 3.37

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 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
PAH	NM_000277.3 linkuse as main transcript	c.165del	p.Phe55LeufsTer6	frameshift_variant	2/13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2 linkuse as main transcript	c.165del	p.Phe55LeufsTer6	frameshift_variant	3/14		NP_001341233.1
PAH	XM_017019370.2 linkuse as main transcript	c.165del	p.Phe55LeufsTer6	frameshift_variant	2/7		XP_016874859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6 linkuse as main transcript	c.165del	p.Phe55LeufsTer6	frameshift_variant	2/13	1	NM_000277.3	ENSP00000448059	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152192

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:

0.0000119

AC:

AN:

251384

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135858

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:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000193

AC:

AN:

1451622

Hom.:

Cov.:

AF XY:

0.0000277

AC XY:

AN XY:

722902

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:

0.0000245

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74360

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

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000189

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 01, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 03, 2016	Variant summary: The c.165delT (p.Phe55Leufs) variant in PAH gene is a frameshift change that results in the loss of the 393 amino acids of PAH (~85%). This change is predicted to cause loss of normal protein function through protein truncation or nonsense-mediated mRNA decay. According to the PAH enzymatic activity prediction it is expected to have a residual activity of 0%, which then will lead to elevated level of plasma Phe concentration. These predictions are in line with biochemical data observed in pts homozygous for c.165delT and presented with Classical PKU phenotype (MR, aphasia, elevated Phe plasma level ranging from 1477-2844umol/l). The variant is present in the large control population dataset of ExAC at a low frequency 0.000016 (2/121380 chrs tested). This frequency does not exceed the maximal expected frequency of a pathogenic allele (0.0079) in this gene. The variant has been reported in multiple affected individuals homozygously or in compound heterozygosity via published reports and has been cited as Pathogenic by several reputable databases/clinical laboratories. Taken together, the variant was classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 10, 2023	This sequence change creates a premature translational stop signal (p.Phe55Leufs*6) 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 (rs199475566, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with hyperphenylalaninemia and/or phenylketonuria (PMID: 1682235, 18346471, 23500595). ClinVar contains an entry for this variant (Variation ID: 611). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 1991	- -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Jul 23, 2019	- -
Pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Apr 03, 2019	The c.165delT (p.F55Lfs*6) is a frameshift variant in exon 2 of 13 in PAH, predicted to undergo nonsense mediated decay with the truncated region critical to protein function. It has been reported in compound heterozygote state in multiple patients with PKU (BH4 deficiency not excluded) (PMID: 1682235 & 23500595). The variants in trans include: R408W, and R261Q, both confirmed pathogenic.This variant has an extremely low allele frequency in the Genome Aggregation database (3/251384) (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria: PM2, PP4, PVS1. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided

Pathogenic:4Other:1

not provided, no classification provided	literature only	DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 27, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 05, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 22, 2023	Reported multiple times in various populations in association with a classic phenylketonuria (PKU) phenotype (Eigel et al. 1991; Alibakhshi et al. 2014; Groselj et al. 2012; Georgiou et al. 2012; Jeannesson-Thivisol et al. 2015; Sterl et al. 2013); 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 a significant frequency in large population cohorts (gnomAD); Described as not responsive to tetrahydrobiopterin therapy (Sarkissian et al., 2012); This variant is associated with the following publications: (PMID: 23856132, 16198137, 12655553, 23500595, 1682235, 24048906, 22513348, 22330942, 26481238, 22526846, 24350308, 23357515, 21147011, 19609714, 19394257, 12655550, 10394930, 9781015, 18346471, 18299955, 26666653, 23430918, 32905092, 33465300, 32778825, 34828281, 35405047) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	PAH: PVS1, PM2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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