rs62514933

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 7 ACMG points: 7P and 0B. PP3PP4PP1PM3PM2

This summary comes from the ClinGen Evidence Repository: The c.653G>T (p.Gly218Val) variant in PAH has been reported in multiple individuals with PAH deficiency (PMID:8406445, 9781015, 10479481). This variant has an extremely low allele frequency (MAF=0.00004) in gnomAD. It was detected with multiple pathogenic variants: p.R158Q, p.I65T (PMID:10479481); p.Y414C (PMID:8632937); c.1066-11G>A, p.Arg270Lys, (PMID:26666653); p.P281L (PMID:24368688); p.R408W (PMID:11032331); p.S349P (PMID:22841515); c.1223G > A (p.R408Q) (PMID:29102225). It co-segregated with disease (PKU) in 2 sisters (PMID:8831077). Computational prediction tools and conservation analysis support a deleterious effect on the protein. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PM2, PP1, PP3, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229676/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

13

3

2

Clinical Significance

Pathogenic reviewed by expert panel P:10O:1

Conservation

PhyloP100: 7.91

Publications

10 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: Pathogenic. The variant received 7 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000277.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAH	NM_000277.3	MANE Select	c.653G>T	p.Gly218Val	missense	Exon 6 of 13	NP_000268.1
	PAH	NM_001354304.2		c.653G>T	p.Gly218Val	missense	Exon 7 of 14	NP_001341233.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAH	ENST00000553106.6	TSL:1 MANE Select	c.653G>T	p.Gly218Val	missense	Exon 6 of 13	ENSP00000448059.1
	PAH	ENST00000549111.5	TSL:1	n.749G>T		non_coding_transcript_exon	Exon 6 of 6
	PAH	ENST00000906695.1		c.653G>T	p.Gly218Val	missense	Exon 6 of 14	ENSP00000576754.1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

2

AN:

152194

Hom.:

0

Cov.:

33

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000119

AC:

3

AN:

251318

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.0000615

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000356

AC:

52

AN:

1461858

Hom.:

0

Cov.:

34

AF XY:

0.0000399

AC XY:

29

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.0000299

AC:

1

AN:

33480

American (AMR)

AF:

0.00

AC:

0

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

0

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

0

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

0

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

0

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

0

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000459

AC:

51

AN:

1111986

Other (OTH)

AF:

0.00

AC:

0

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

0

3

6

8

11

14

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

0

4

8

12

16

20

<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

AF:

0.0000131

AC:

2

AN:

152194

Hom.:

0

Cov.:

33

AF XY:

0.0000134

AC XY:

1

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.0000241

AC:

1

AN:

41428

American (AMR)

AF:

0.00

AC:

0

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

0

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

0

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

0

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

0

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

0

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

1

AN:

68042

Other (OTH)

AF:

0.00

AC:

0

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0

0

1

1

2

2

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:

0.0000307

Hom.:

0

Bravo

AF:

0.0000151

ExAC

AF:

0.0000165

AC:

2

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

7

-

-

Phenylketonuria (7)

1

-

-

Inborn genetic diseases (1)

1

-

-

not provided (2)

1

-

-

PAH-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Pathogenic

0.43

D

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

29

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.98

D

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.99

D

LIST_S2

Pathogenic

0.98

D

M_CAP

Pathogenic

0.34

D

MetaRNN

Pathogenic

0.98

D

MetaSVM

Pathogenic

1.1

D

MutationAssessor

Pathogenic

3.4

M

PhyloP100

7.9

PrimateAI

Uncertain

0.57

T

PROVEAN

Pathogenic

-8.3

D

REVEL

Pathogenic

0.93

Sift

Uncertain

0.020

D

Sift4G

Benign

0.084

T

Polyphen

1.0

D

Vest4

0.96

MVP

0.97

MPC

0.26

ClinPred

1.0

D

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.96

gMVP

0.97

Mutation Taster

=0/100

disease causing (ClinVar)

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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Other links and lift over

dbSNP: rs62514933; hg19: chr12-103248967; API