rs199475580

Positions:

• chr12-102852866-T-A
• chr12-102852866-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

This summary comes from the ClinGen Evidence Repository: The c.791A>T (p.His264Leu) variant in PAH has not been reported in the literature, to our knowledge. References in BioPKU/PAHdb (Cardoso 2001) cannot be located. This variant is absent from ExAC, GnomAD, 1000G, and ESP. It is predicted deleterious in SIFT, Polyphen2, MutationTaster, and REVEL=0.949. The H264 residue interacts directly with the BH4 cofactor. (PMID:12126628). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM1, PM2, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229761/MONDO:0009861/006

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAH ENST00000553106.6 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:1 O:1
• Conservation: PhyloP100: 8.02

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: 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.791A>T	p.His264Leu	missense_variant	7/13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.791A>T	p.His264Leu	missense_variant	8/14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.791A>T	p.His264Leu	missense_variant	7/13	1	NM_000277.3	ENSP00000448059	P1
PAH	ENST00000307000.7	c.776A>T	p.His259Leu	missense_variant	8/14	5		ENSP00000303500
PAH	ENST00000549247.6	n.550A>T		non_coding_transcript_exon_variant	1/6	2
PAH	ENST00000635477.1			upstream_gene_variant		5		ENSP00000489230

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen PAH Variant Curation Expert Panel

Dec 10, 2018

The c.791A>T (p.His264Leu) variant in PAH has not been reported in the literature, to our knowledge. References in BioPKU/PAHdb (Cardoso 2001) cannot be located. This variant is absent from ExAC, GnomAD, 1000G, and ESP. It is predicted deleterious in SIFT, Polyphen2, MutationTaster, and REVEL=0.949. The H264 residue interacts directly with the BH4 cofactor. (PMID: 12126628). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM1, PM2, PP3. -

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
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	28
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.98	D;D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.2	H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-10	D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.050	T;T
Polyphen		1.0	D;.
Vest4		0.81
MutPred		0.92		Loss of catalytic residue at H264 (P = 0.0747);.;
MVP		0.97
MPC		0.26
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.98
gMVP		0.98

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: rs199475580; hg19: chr12-103246644;