12-102843769-G-C

Position:

• chr12-102843769-G-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP4_Moderate PVS1 PM2

This summary comes from the ClinGen Evidence Repository: The c.1076C>G (p.Ser359Ter) variant in PAH has been reported in an individual with PKU; BH4 deficiency excluded (PP4_Moderate; PMID:8097261; (PMID:9634518). This variant is absent in population databases (PM2). It is a nonsense variant in exon 11 of 13 in PAH, predicted to undergo nonsense mediated decay with the truncated region critical to protein function (PVS1). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229330/MONDO:0009861/006

• Frequency: Genomes: not found (cov: 31)
• Consequence: PAH NM_000277.3 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:3 O:1
• Conservation: PhyloP100: 9.98

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 12 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.1076C>G	p.Ser359*	stop_gained	11/13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.1076C>G	p.Ser359*	stop_gained	12/14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.1076C>G	p.Ser359*	stop_gained	11/13	1	NM_000277.3	ENSP00000448059.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2023	For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Ser359*) 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 phenylketonuria (PMID: 8097261, 32668217). ClinVar contains an entry for this variant (Variation ID: 626). -
Pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Jun 26, 2020	The c.1076C>G (p.Ser359Ter) variant in PAH has been reported in an individual with PKU; BH4 deficiency excluded (PP4_Moderate; PMID: 8097261; (PMID: 9634518). This variant is absent in population databases (PM2). It is a nonsense variant in exon 11 of 13 in PAH, predicted to undergo nonsense mediated decay with the truncated region critical to protein function (PVS1). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4_Moderate. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 1993	- -

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	0.66
CADD	Pathogenic	44
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	1.0	D
Vest4		0.94
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs5030854; hg19: chr12-103237547;