rs62516060

Positions:

chr12-102844404-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM3_StrongPS3_SupportingPM2PP4_ModeratePP3

This summary comes from the ClinGen Evidence Repository: The c.997C>T (p.Leu333Phe) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded). It was detected with multiple pathogenic variants: p.E390G (PMID:8098245); p.R261Q (PMID:21147011); p.S110L (LP by PAH VCEP, PMID:26542770). This variant is absent in population databases. In an eukaryotic expression system, the L333F mutant had 7% PAH activity as compared to wild type (PMID:10479481). Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as Pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PP4_Moderate, PM2, PP3, PS3_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA114366/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PAH
ENST00000553106.6 missense

Scores

10

7

2

Clinical Significance

Pathogenic reviewed by expert panel P:5O:1

Conservation

PhyloP100: 5.70

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PS3

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.

PP3

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 linkuse as main transcript	c.997C>T	p.Leu333Phe	missense_variant	10/13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2 linkuse as main transcript	c.997C>T	p.Leu333Phe	missense_variant	11/14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6 linkuse as main transcript	c.997C>T	p.Leu333Phe	missense_variant	10/13	1	NM_000277.3	ENSP00000448059	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

1

AN:

152144

Hom.:

0

Cov.:

32

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

1

AN:

1461162

Hom.:

0

Cov.:

31

AF XY:

0.00

AC XY:

0

AN XY:

726918

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

1

AN:

152144

Hom.:

0

Cov.:

32

AF XY:

0.0000135

AC XY:

1

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:4

Pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Mar 13, 2022	The c.997C>T (p.Leu333Phe) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded). It was detected with multiple pathogenic variants: p.E390G (PMID: 8098245); p.R261Q (PMID: 21147011); p.S110L (LP by PAH VCEP, PMID: 26542770). This variant is absent in population databases. In an eukaryotic expression system, the L333F mutant had 7% PAH activity as compared to wild type (PMID: 10479481). Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as Pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PP4_Moderate, PM2, PP3, PS3_supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 02, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences	Sep 19, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 27, 2023	Variant summary: PAH c.997C>T (p.Leu333Phe) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain (IPR019774) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251062 control chromosomes. c.997C>T has been reported in the literature as a biallelic genotype in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (example, Abadie_1993, Benit_1999, Zare-Karizi_2011, Bayat_2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 7% of normal PAH enzyme activity in vitro (Benit_1999). The following publications have been ascertained in the context of this evaluation (PMID: 8098245, 26542770, 10479481, 20920871). One expert panel (ClinGen PAH Variant Curation Expert Panel) has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Hyperphenylalaninemia

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 1993

- -

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

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Pathogenic

0.54

D

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

29

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.99

D;D

Eigen

Pathogenic

0.74

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.95

D

LIST_S2

Benign

0.80

T;T

M_CAP

Pathogenic

0.88

D

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

0.91

D

MutationAssessor

Pathogenic

4.1

H;.

MutationTaster

Benign

1.0

A;A

PrimateAI

Uncertain

0.74

T

PROVEAN

Uncertain

-3.3

D;D

REVEL

Pathogenic

0.95

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;.

Vest4

0.94

MutPred

0.96

Gain of ubiquitination at K335 (P = 0.0828);.;

MVP

0.97

MPC

0.24

ClinPred

1.0

D

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.88

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs62516060; hg19: chr12-103238182;