rs62516101

chr12-102843683-C-Gchr12-102843683-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000277.3(PAH):c.1162G>C(p.Val388Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V388A) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:2 O:1
• Conservation: PhyloP100: 5.04

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 18 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000277.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-102843682-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 120260.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 12-102843683-C-G is Pathogenic according to our data. Variant chr12-102843683-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 102541.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr12-102843683-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAH	NM_000277.3	c.1162G>C	p.Val388Leu	missense_variant	11/13	ENST00000553106.6
PAH	NM_001354304.2	c.1162G>C	p.Val388Leu	missense_variant	12/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAH	ENST00000553106.6	c.1162G>C	p.Val388Leu	missense_variant	11/13	1	NM_000277.3	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:1 Other:1

not provided, no classification provided	literature only	DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 17, 2016	The V388L variant has been reported in a Korean patient with PKU who also harbored a second missense variant in the PAH gene (Park et al. 1998). The V388L variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position that is conserved across species, and a missense variant at the same position (V388M) has been reported in the Human Gene Mutation Database in association with PKU (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, the V388L variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. -

Phenylketonuria Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen PAH Variant Curation Expert Panel

Oct 16, 2020

This c.1162G>C (p.Val388Leu) variant in PAH was reported in 3 patients with PAH deficiency (PMID: 27121329, 31623983) detected with the likely pathogenic variant p.Pro281Leu and the pathogenic variant p.Arg252Trp. DHPR activity, biopterin and/or pteridine analysis was performed to rule out other causes of hyperphenylalaninemia (PMID: 27121329). This variant is a novel missense change at an amino acid residue where a different missense change p.Val388Met determined to be pathogenic has been seen before. This variant is present in Dominican populations at a minor allele frequency of 0.00052 (PAGE study). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PM5, PP4_moderate. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
Cadd	Benign	20
Dann	Uncertain	0.98
DEOGEN2	Pathogenic	0.90	D;D
Eigen	Benign	0.027
Eigen_PC	Benign	0.13
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.8	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.5	N;N
REVEL	Pathogenic	0.68
Sift	Benign	0.10	T;T
Sift4G	Benign	0.16	T;T
Polyphen		0.078	B;.
Vest4		0.84
MutPred		0.94		Loss of sheet (P = 0.0817);.;
MVP		0.96
MPC		0.042
ClinPred		0.77	D
GERP RS		5.3
Varity_R		0.74
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs62516101; hg19: chr12-103237461;