rs199475676

Variant names:

• chr12-102852858-G-A
• rs199475676
• NM_000277.3:c.799C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-102852858-G-A
• chr12-102852858-G-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PVS1 PP4_Moderate PM3_Strong

This summary comes from the ClinGen Evidence Repository: The PAH variant c.799C>T (p.Gln267Ter) is a null variant (stop gain) located in exon number 7 of the PAH gene. Loss of function in the PAH gene is a mechanism of disease. Eleven null variants in exon 7 of the PAH gene have been reported. The mRNA transcript is predicted to undergo NMD.The variant c.799C>T (p.Gln267Ter) was reported in trans with the pathogenic PAH variant c.442-1G>A (ClinVar ID: 594) in a Chinese patient with classic PKU (Phe levels >20 mg/dl). BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes. (PMID:26322415). The PAH variant c.799C>T (p.Gln267Ter) was also reported in trans with the pathogenic PAH variant IVS10‐11G>A (ClinVar ID: 607) in a Brazilian patient with classic PKU (PMID:18798839) PM3_Strong (2.0). The variant c.799C>T (p.Gln267Ter) is absent from the gnomAD, ExAC, PAGE, and ESP population databases. In summary, this variant meets the criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3_Strong, PVS1, PP4-moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16020861/MONDO:0009861/006

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAH NM_000277.3 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 10.0

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 16 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 rank	MANE	Protein	UniProt
PAH	NM_000277.3	c.799C>T	p.Gln267*	stop_gained	Exon 7 of 13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.799C>T	p.Gln267*	stop_gained	Exon 8 of 14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.799C>T	p.Gln267*	stop_gained	Exon 7 of 13	1	NM_000277.3	ENSP00000448059.1
PAH	ENST00000307000.7	c.784C>T	p.Gln262*	stop_gained	Exon 8 of 14	5		ENSP00000303500.2
PAH	ENST00000549247.6	n.558C>T		non_coding_transcript_exon_variant	Exon 1 of 6	2
PAH	ENST00000635477.1	c.-42C>T		upstream_gene_variant		5		ENSP00000489230.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:2

May 09, 2020

ClinGen PAH Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The PAH variant c.799C>T (p.Gln267Ter) is a null variant (stop gain) located in exon number 7 of the PAH gene. Loss of function in the PAH gene is a mechanism of disease. Eleven null variants in exon 7 of the PAH gene have been reported. The mRNA transcript is predicted to undergo NMD. The variant c.799C>T (p.Gln267Ter) was reported in trans with the pathogenic PAH variant c.442-1G>A (ClinVar ID: 594) in a Chinese patient with classic PKU (Phe levels >20 mg/dl). BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes. (PMID: 26322415). The PAH variant c.799C>T (p.Gln267Ter) was also reported in trans with the pathogenic PAH variant IVS10-11G>A (ClinVar ID: 607) in a Brazilian patient with classic PKU (PMID: 18798839) PM3_Strong (2.0). The variant c.799C>T (p.Gln267Ter) is absent from the gnomAD, ExAC, PAGE, and ESP population databases. In summary, this variant meets the criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3_Strong, PVS1, PP4-moderate. -

Nov 05, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been observed in several individuals affected with PKU (PMID: 26322415, 18798839). This sequence change creates a premature translational stop signal (p.Gln267*) in the PAH gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). Loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	48
DANN	Uncertain	1.0
Eigen	Pathogenic	1.3
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
Vest4		0.92
GERP RS		5.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs199475676; hg19: chr12-103246636; COSMIC: COSV61019636; COSMIC: COSV61019636;