rs62517201

Positions:

• chr12-102855224-G-C
• chr12-102855224-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM3 PVS1 PM2 PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The c.618C>G (p.Tyr206Ter) variant in PAH is a null variant (nonsense variant) in exon 6 of 13 in a gene where LOF is a known mechanism of disease, leading to premature truncation and NMD (PVS1). It is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). It has been reported in at least six PKU patients (per abnormal blood Phe levels) (PP4), including in trans with pathogenic variants: with R158Q (pathogenic per PAH VCEP) (PMID:30829006); homozygous in an Indian case with classic PKU (PMID:24130151); in trans with the known pathogenic (per PAH VCEP) p.R408W variant (PMID:9452062); in a Chinese PKU case in trans with the known pathogenic (per PAH VCEP) EX6-96A>G variant (PMID:16256386); and in two Spanish patients, in trans with the pathogenic (per PAH VCEP) Thr380Met and the p.Ala309Val variants, respectively (PMID:27121329) (PM3_VeryStrong). It has also been reported Likely Pathogenic by one lab in ClinVar (variation ID 102763). Classification: PathogenicSupporting criteria: PVS1, PM2; PM3_VeryStrong; PP4 LINK:https://erepo.genome.network/evrepo/ui/classification/CA229662/MONDO:0009861/006

• Frequency: Genomes: not found (cov: 33)
• Consequence: PAH ENST00000553106.6 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:2 O:1
• Conservation: PhyloP100: 5.94

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 14 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.618C>G	p.Tyr206Ter	stop_gained	6/13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.618C>G	p.Tyr206Ter	stop_gained	7/14		NP_001341233.1
PAH	XM_017019370.2	c.618C>G	p.Tyr206Ter	stop_gained	6/7		XP_016874859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.618C>G	p.Tyr206Ter	stop_gained	6/13	1	NM_000277.3	ENSP00000448059	P1
PAH	ENST00000549111.5	n.714C>G		non_coding_transcript_exon_variant	6/6	1
PAH	ENST00000307000.7	c.603C>G	p.Tyr201Ter	stop_gained	7/14	5		ENSP00000303500

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:2

Pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Apr 13, 2020	The c.618C>G (p.Tyr206Ter) variant in PAH is a null variant (nonsense variant) in exon 6 of 13 in a gene where LOF is a known mechanism of disease, leading to premature truncation and NMD (PVS1). It is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). It has been reported in at least six PKU patients (per abnormal blood Phe levels) (PP4), including in trans with pathogenic variants: with R158Q (pathogenic per PAH VCEP) (PMID: 30829006); homozygous in an Indian case with classic PKU (PMID: 24130151); in trans with the known pathogenic (per PAH VCEP) p.R408W variant (PMID: 9452062); in a Chinese PKU case in trans with the known pathogenic (per PAH VCEP) EX6-96A>G variant (PMID: 16256386); and in two Spanish patients, in trans with the pathogenic (per PAH VCEP) Thr380Met and the p.Ala309Val variants, respectively (PMID: 27121329) (PM3_VeryStrong). It has also been reported Likely Pathogenic by one lab in ClinVar (variation ID 102763). Classification: Pathogenic Supporting criteria: PVS1, PM2; PM3_VeryStrong; PP4 -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneID Lab - Advanced Molecular Diagnostics	Sep 07, 2017	- -

not provided Other:1

not provided, no classification provided

literature only

DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	A;A
Vest4		0.93
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs62517201; hg19: chr12-103249002;