12-102866612-C-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PP1PP3PM3PP4_ModeratePM2

This summary comes from the ClinGen Evidence Repository: The c.493G>A (p.Ala165Thr) variant in PAH has been reported in multiple individuals with PKU, including siblings (BH4 deficiency excluded). (PP4_Moderate, PMID:8981952; PP1, PMID:26666653). This variant has extremely low frequency in gnomAD (MAF=0.00001) (PM2). This variant was detected with c.1066-11G>A (PM3; PMID:10598814). Multiple lines of computational evidence support a deleterious effect (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP1, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229579/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

13

5

1

Clinical Significance

Likely pathogenic reviewed by expert panel P:2O:1

Conservation

PhyloP100: 5.24

Publications

5 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:

LOC124902999 (HGNC:):

LOC124902999 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

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.

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.493G>A	p.Ala165Thr	missense_variant	Exon 5 of 13	ENST00000553106.6	NP_000268.1	P00439A0A024RBG4
PAH	NM_001354304.2 link	c.493G>A	p.Ala165Thr	missense_variant	Exon 6 of 14		NP_001341233.1
PAH	XM_017019370.2 link	c.493G>A	p.Ala165Thr	missense_variant	Exon 5 of 7		XP_016874859.1
LOC124902999	XR_007063428.1 link	n.807+1385C>T		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6 link	c.493G>A	p.Ala165Thr	missense_variant	Exon 5 of 13	1	NM_000277.3	ENSP00000448059.1		P00439
PAH	ENST00000549111.5 link	n.589G>A		non_coding_transcript_exon_variant	Exon 5 of 6	1
PAH	ENST00000307000.7 link	c.478G>A	p.Ala160Thr	missense_variant	Exon 6 of 14	5		ENSP00000303500.2		J3KND8
PAH	ENST00000551988.5 link	n.530+10850G>A		intron_variant	Intron 4 of 4	3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

2

AN:

152126

Hom.:

0

Cov.:

32

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000398

AC:

1

AN:

251346

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

4

AN:

1461362

Hom.:

0

Cov.:

30

AF XY:

0.00000413

AC XY:

3

AN XY:

727010

show subpopulations

African (AFR)

AF:

0.00

AC:

0

AN:

33456

American (AMR)

AF:

0.00

AC:

0

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

0

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

0

AN:

39692

South Asian (SAS)

AF:

0.0000116

AC:

1

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

0

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

0

AN:

5764

European-Non Finnish (NFE)

AF:

0.00000270

AC:

3

AN:

1111588

Other (OTH)

AF:

0.00

AC:

0

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0

1

2

2

3

4

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000131

AC:

2

AN:

152126

Hom.:

0

Cov.:

32

AF XY:

0.00

AC XY:

0

AN XY:

74310

show subpopulations

African (AFR)

AF:

0.00

AC:

0

AN:

41428

American (AMR)

AF:

0.00

AC:

0

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

0

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

0

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

0

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

0

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

0

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

2

AN:

68022

Other (OTH)

AF:

0.00

AC:

0

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0

1

1

2

2

3

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

0

2

4

6

8

10

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

0

Bravo

AF:

0.00000756

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:2

Apr 07, 2019

ClinGen PAH Variant Curation Expert Panel

Significance:Likely pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

The c.493G>A (p.Ala165Thr) variant in PAH has been reported in multiple individuals with PKU, including siblings (BH4 deficiency excluded). (PP4_Moderate, PMID: 8981952; PP1, PMID: 26666653). This variant has extremely low frequency in gnomAD (MAF=0.00001) (PM2). This variant was detected with c.1066-11G>A (PM3; PMID: 10598814). Multiple lines of computational evidence support a deleterious effect (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP1, PP3. -

Jun 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 165 of the PAH protein (p.Ala165Thr). This variant is present in population databases (rs199475626, gnomAD 0.0009%). This missense change has been observed in individual(s) with phenylketonuria (PMID: 26666653). ClinVar contains an entry for this variant (Variation ID: 102700). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PAH protein function with a positive predictive value of 80%. 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

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Pathogenic

0.53

D

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

29

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

1.0

D;D

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Uncertain

0.96

D

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.78

D

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

0.96

D

MutationAssessor

Pathogenic

4.1

H;.

PhyloP100

5.2

PrimateAI

Uncertain

0.68

T

PROVEAN

Uncertain

-3.9

D;D

REVEL

Pathogenic

0.94

Sift

Uncertain

0.0080

D;D

Sift4G

Uncertain

0.0080

D;D

Polyphen

1.0

D;.

Vest4

0.94

MutPred

0.97

Loss of stability (P = 0.0687);.;

MVP

0.99

MPC

0.23

ClinPred

0.99

D

GERP RS

6.1

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.0

Varity_R

0.64

gMVP

0.96

Mutation Taster

=4/96

disease causing (ClinVar)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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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Other links and lift over

dbSNP: rs199475626; hg19: chr12-103260390; API