rs5030654

Positions:

• chr12-102843755-GC-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PP4 PVS1 PM2

This summary comes from the ClinGen Evidence Repository: PAH-specific ACMG/AMP criteria applied: PVS1: Frameshift variant; PM2: Absent from ExAC, gnomAD, 1000G, ESP; PP4: Detected in a patient with Classical PKU. (PMID:8659548). 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/CA229336/MONDO:0009861/006

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: PAH NM_000277.3 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:12 O:1
• Conservation: PhyloP100: -0.107

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.

• 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	c.1089delG	p.Lys363fs	frameshift_variant	11/13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.1089delG	p.Lys363fs	frameshift_variant	12/14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.1089delG	p.Lys363fs	frameshift_variant	11/13	1	NM_000277.3	ENSP00000448059.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461598 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727120

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: 8.99e-7

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12 Other:1

Revision: reviewed by expert panel

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: Absent from ExAC, gnomAD, 1000G, ESP; PP4: Detected in a patient with Classical PKU. (PMID:8659548). 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	Baylor Genetics	Mar 10, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 03, 2022	The p.Lys363AsnfsX37 in PAH has been reported in at least 12 homozygous and 1 compound heterozygous individuals affected with Hyperphenylalaninemia or Phenylketonuria (selected publications: Carducci 2020 PMID: 32905092, Zare-Karizi 2011 PMID: 20920871, Kostandyan 2011 PMID: 21890392, Alibakhshi 2014 PMID: 24048906). This variant was classified as Pathogenic on August 10, 2018 by the ClinGen-approved ClinGen PAH Variant Curation Expert Panel (Variation ID 102518) and was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 363 and leads to a premature termination codon 37 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the PAH gene is an established disease mechanism in autosomal recessive Phenylketonuria. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hyperphenylalanemia/phenylkenonuria. ACMG/AMP Criteria applied: PM2_Supporting, PVS1, PM3_Strong. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 05, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	This sequence change creates a premature translational stop signal (p.Lys363Asnfs*37) 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 individuals with phenylketonuria (PMID: 8889590, 20920871, 21890392, 24048906). ClinVar contains an entry for this variant (Variation ID: 102518). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 14, 2016	Variant summary: The PAH c.1089delG (p.Lys363Glnfs) variant results in a premature termination codon, predicted to cause a truncated or absent PAH protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant has been reported in numerous PKU and HPA patients and is absent in 121252 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	-	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Oct 14, 2014	- -

not provided Pathogenic:3 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	PAH: PVS1, PM2, PM3:Supporting, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 17, 2022	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: 9792407, 17096675, 22513348, 8659548, 20920871, 21147011, 9781015, 26481238, 18299955, 28676969, 29499199, 32905092, 31589614, 32778825, 24048906) -
not provided, no classification provided	literature only	DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 14, 2018	- -

Computational scores

Source: dbNSFP v4.3

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: rs5030654; hg19: chr12-103237533;