rs199475645

Positions:

• chr12-102866607-G-C
• chr12-102866607-G-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM3_Supporting PM2 PVS1 PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The c.498C>G (p.Tyr166Ter) variant in PAH is a nonsense variant in exon 5 of 13 in PAH, predicted to undergo nonsense mediated decay. It has been reported in multiple individuals, including in homozygosity in a classic PKU patient in the Uyger population. (PM3, PP4, PMID:31355225). This variant is absent from ExAC/gnomAD, 1000 Genomes, and ESP (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3_supporting, PP4_moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16020801/MONDO:0009861/006

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAH NM_000277.3 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 1.46

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]

LOC124902999 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 13 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	UniProt
PAH	NM_000277.3	c.498C>G	p.Tyr166Ter	stop_gained	5/13	ENST00000553106.6	NP_000268.1
LOC124902999	XR_007063428.1	n.807+1380G>C		intron_variant, non_coding_transcript_variant
PAH	NM_001354304.2	c.498C>G	p.Tyr166Ter	stop_gained	6/14		NP_001341233.1
PAH	XM_017019370.2	c.498C>G	p.Tyr166Ter	stop_gained	5/7		XP_016874859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.498C>G	p.Tyr166Ter	stop_gained	5/13	1	NM_000277.3	ENSP00000448059	P1
PAH	ENST00000549111.5	n.594C>G		non_coding_transcript_exon_variant	5/6	1
PAH	ENST00000307000.7	c.483C>G	p.Tyr161Ter	stop_gained	6/14	5		ENSP00000303500
PAH	ENST00000551988.5	n.530+10855C>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 21, 2024	This sequence change creates a premature translational stop signal (p.Tyr166*) 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 hyperphenylalaninemia and/or phenylketonuria (PMID: 16256386, 28754886, 29176022). ClinVar contains an entry for this variant (Variation ID: 371373). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jul 05, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 28, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Sep 07, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 07, 2022	Variant summary: PAH c.498C>G (p.Tyr166X) 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 was absent in 251362 control chromosomes (gnomAD). The variant c.498C>G has been reported in the literature in several homozygous and compound heterozygous individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (e.g. Zhu_2013, Tao_2015, Li_2018, Xiao_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar, and both of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Jan 22, 2022	The c.498C>G (p.Tyr166Ter) variant in PAH is a nonsense variant in exon 5 of 13 in PAH, predicted to undergo nonsense mediated decay. It has been reported in multiple individuals, including in homozygosity in a classic PKU patient in the Uyger population. (PM3, PP4, PMID:31355225). This variant is absent from ExAC/gnomAD, 1000 Genomes, and ESP (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3_supporting, PP4_moderate. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.92	D
MutationTaster	Benign	1.0	A;A
Vest4		0.88
GERP RS		3.0
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs199475645; hg19: chr12-103260385;