12-102843745-A-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PP3PP4_ModeratePM2

This summary comes from the ClinGen Evidence Repository: The c.1100T>C (p.Leu367Pro) variant in PAH is reported in a Japanese patient with PKU, BH4 deficiency was excluded. (PMID:21307867) This variant is absent in population databases. It is predicted deleterious by SIFT, Polyphen-2 and MutationTaster. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229344/MONDO:0009861/006

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:2O:1

Conservation

PhyloP100: 9.32

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

phenylketonuria
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Myriad Women’s Health
classic phenylketonuria
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
maternal phenylketonuria
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
mild hyperphenylalaninemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
mild phenylketonuria
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
tetrahydrobiopterin-responsive hyperphenylalaninemia/phenylketonuria
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PAH links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

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 rank	MANE	Protein	UniProt
PAH	NM_000277.3 link	c.1100T>C	p.Leu367Pro	missense_variant	Exon 11 of 13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2 link	c.1100T>C	p.Leu367Pro	missense_variant	Exon 12 of 14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6 link	c.1100T>C	p.Leu367Pro	missense_variant	Exon 11 of 13	1	NM_000277.3	ENSP00000448059.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461556

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727094

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33464

American (AMR)

AF:

0.00

AC:

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111760

Other (OTH)

AF:

0.00

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 16, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: PAH c.1100T>C (p.Leu367Pro) results in a non-conservative amino acid change located in the Biopterin-dependent aromatic amino acid hydroxylase 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 251232 control chromosomes. c.1100T>C has been reported in the literature in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (Okano_2011, Odagiri_2021). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33803550, 21307867). ClinVar contains an entry for this variant (Variation ID: 102525). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

Phenylketonuria

Uncertain:1

Dec 08, 2018

ClinGen PAH Variant Curation Expert Panel

Significance:Uncertain significance

Review Status:reviewed by expert panel

Collection Method:curation

The c.1100T>C (p.Leu367Pro) variant in PAH is reported in a Japanese patient with PKU, BH4 deficiency was excluded. (PMID: 21307867) This variant is absent in population databases. It is predicted deleterious by SIFT, Polyphen-2 and MutationTaster. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PP3.

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

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.57

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

1.0

D;D

Eigen

Pathogenic

0.73

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

D;D

M_CAP

Pathogenic

0.93

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.8

M;.

PhyloP100

9.3

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-4.1

D;D

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.013

D;D

Vest4

0.91

ClinPred

1.0

GERP RS

5.2

Varity_R

0.92

gMVP

0.99

Mutation Taster

=22/78

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over