12-102917128-C-T

Variant names:

• chr12-102917128-C-T
• rs62514893
• NM_000277.3:c.3G>A

Variant summary

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

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 rank	MANE	Protein	UniProt
PAH	NM_000277.3	c.3G>A	p.Met1?	start_lost	Exon 1 of 13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.3G>A	p.Met1?	start_lost	Exon 2 of 14		NP_001341233.1
PAH	XM_017019370.2	c.3G>A	p.Met1?	start_lost	Exon 1 of 7		XP_016874859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.3G>A	p.Met1?	start_lost	Exon 1 of 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

Jul 07, 2019

ClinGen PAH Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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. -

Jan 01, 1992

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 29, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the PAH mRNA. The next in-frame methionine is located at codon 180. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with hyperphenylalaninemia (PMID: 1301947, 10679941, 32668217). ClinVar contains an entry for this variant (Variation ID: 622). For these reasons, this variant has been classified as Pathogenic. -

not provided Other:1

-

DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

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;