12-102917128-C-T

Position:

• chr12-102917128-C-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PS2_Moderate PP1 PP4_Moderate PVS1 PM2 PM3_Strong

This summary comes from the ClinGen Evidence Repository: The c.3G>A (p.Met1Ile) variant is a null variant (start loss) where LOF is a known mechanism of disease. There are no known alternative start codons in other transcripts. The next in-frame Met is at amino acid 180 in exon 6. There are 49 pathogenic variants in ClinVar upstream of aa 180. The p.Met1Val variant has <3% enzyme activity as compared to wild type (PMID:9450897), confirming start loss variants lead to loss of function of the PAH enzyme without re-initiation. This variant has been detected in multiple patients with PKU, BH4 deficiency excluded. PMID:1301947, 23514811 (PP4_Moderate). This variant is absent in population databases (PM2). This variant was detected in trans with pathogenic variants IVS12+1G>A (PMID:1301947) and p.F55L (27121329) (PM3_Strong). This variant has been detected de novo (PS2_moderate; PMID:1301947), and in affected siblings (PP1; 23514811) In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PVS1, PM2, PP4_Moderate, PS2_moderate, PP1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229532/MONDO:0009861/006

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAH NM_000277.3 start_lost
• Clinical Significance: Pathogenic reviewed by expert panel P:3 O:1
• Conservation: PhyloP100: 3.26

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 19 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS2: 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.
• PP1: 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.3G>A	p.Met1?	start_lost	1/13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.3G>A	p.Met1?	start_lost	2/14		NP_001341233.1
PAH	XM_017019370.2	c.3G>A	p.Met1?	start_lost	1/7		XP_016874859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.3G>A	p.Met1?	start_lost	1/13	1	NM_000277.3	ENSP00000448059.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1992	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 29, 2022	This sequence change affects the initiator methionine of the PAH mRNA. The next in-frame methionine is located at codon 180. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 622). Disruption of the initiator codon has been observed in individual(s) with hyperphenylalaninemia (PMID: 1301947, 10679941, 32668217). This variant is not present in population databases (gnomAD no frequency). -
Pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Jul 07, 2019	The c.3G>A (p.Met1Ile) variant is a null variant (start loss) where LOF is a known mechanism of disease. There are no known alternative start codons in other transcripts. The next in-frame Met is at amino acid 180 in exon 6. There are 49 pathogenic variants in ClinVar upstream of aa 180. The p.Met1Val variant has <3% enzyme activity as compared to wild type (PMID: 9450897), confirming start loss variants lead to loss of function of the PAH enzyme without re-initiation. This variant has been detected in multiple patients with PKU, BH4 deficiency excluded. PMID: 1301947, 23514811 (PP4_Moderate). This variant is absent in population databases (PM2). This variant was detected in trans with pathogenic variants IVS12+1G>A (PMID: 1301947) and p.F55L (27121329) (PM3_Strong). This variant has been detected de novo (PS2_moderate; PMID: 1301947), and in affected siblings (PP1; 23514811) In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PVS1, PM2, PP4_Moderate, PS2_moderate, PP1. -

not provided Other:1

not provided, no classification provided

literature only

DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.58
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T;T;T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
PROVEAN	Benign	-0.58	N;N;N
REVEL	Uncertain	0.62
Sift	Benign	0.036	D;D;D
Sift4G	Benign	0.15	T;D;.
Polyphen		0.53	P;.;.
Vest4		0.97
MutPred		1.0		Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);
MVP		0.97
ClinPred		0.98	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.72
gMVP		0.66

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: rs62514893; hg19: chr12-103310906;