rs140945592

Positions:

• chr12-102894918-C-A
• chr12-102894918-C-T

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: The c.169G>T (p.Glu57Ter) variant in PAH has been previously reported Likely Pathogenic by one clinical laboratory in ClinVar (see variant ID 120268); the collection method is stated as “literature only” and no further information is provided. With respect to the published literature, it has been previously reported in one proband with classic PKU (defined by the authors as plasma phenylalanine levels > 1200umol/L) (PMID:26666653) (PP4). The proband was said to be heterozygous for the variant and also harbor the known pathogenic allele (per ClinGen PAH working group classification, see ClinVar ID 636) c.194T>C (p.Ile65Thr); however, the manuscript did not specify whether the phase of the variants was confirmed via parental testing. Thus, at this point, PM3 cannot be applied with full confidence.The sequence change results in a nonsense variant which occurs in exon 3 of 13 in the in the canonical transcript of PAH, a gene fulfilling the most recent criteria for LOF being a known disease mechanism (see PMID:30192042) (PVS1). It is present at extremely low frequencies in control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and ESP: the highest MAF reported is 0.00014 in Other subpopulation in gnomAD, below the 0.0002 allele frequency cutoff for PAH variants (PM2). LINK:https://erepo.genome.network/evrepo/ui/classification/CA267642/MONDO:0009861/006

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAH NM_000277.3 stop_gained, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 5.27

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 (HGNC:):

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.169G>T	p.Glu57*	stop_gained, splice_region_variant	3/13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.169G>T	p.Glu57*	stop_gained, splice_region_variant	4/14		NP_001341233.1
PAH	XM_017019370.2	c.169G>T	p.Glu57*	stop_gained, splice_region_variant	3/7		XP_016874859.1
LOC124902999	XR_007063428.1	n.863-9780C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.169G>T	p.Glu57*	stop_gained, splice_region_variant	3/13	1	NM_000277.3	ENSP00000448059.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:2

Pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Sep 29, 2019	The c.169G>T (p.Glu57Ter) variant in PAH has been previously reported Likely Pathogenic by one clinical laboratory in ClinVar (see variant ID 120268); the collection method is stated as 'literature only' and no further information is provided. With respect to the published literature, it has been previously reported in one proband with classic PKU (defined by the authors as plasma phenylalanine levels > 1200umol/L) (PMID: 26666653) (PP4). The proband was said to be heterozygous for the variant and also harbor the known pathogenic allele (per ClinGen PAH working group classification, see ClinVar ID 636) c.194T>C (p.Ile65Thr); however, the manuscript did not specify whether the phase of the variants was confirmed via parental testing. Thus, at this point, PM3 cannot be applied with full confidence. The sequence change results in a nonsense variant which occurs in exon 3 of 13 in the in the canonical transcript of PAH, a gene fulfilling the most recent criteria for LOF being a known disease mechanism (see PMID: 30192042) (PVS1). It is present at extremely low frequencies in control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and ESP: the highest MAF reported is 0.00014 in Other subpopulation in gnomAD, below the 0.0002 allele frequency cutoff for PAH variants (PM2). -
Likely pathogenic, no assertion criteria provided	literature only	Inserm U 954, Faculté de Médecine de Nancy	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	55
DANN	Uncertain	1.0
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.98	D
Vest4		0.86
GERP RS		6.2

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.88		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.88		Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs140945592; hg19: chr12-103288696;