rs62516155

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP3PP4PM5PM3_StrongPM2

This summary comes from the ClinGen Evidence Repository: The c.830A>G (p.Tyr277Cys) variant in PAH has been reported in multiple individuals with PKU (PMID:24350308). This variant has an extremely low allele frequency (MAF=0.00006) in gnomAD. It was detected with multiple pathogenic variants: p.R408W in 2 patients; p.L194P (PMID:24350308); c.842+1G>A in 2 patients (PMID:25952249). Computational prediction tools and conservation analysis support a deleterious effect. Another missense change at the same amino acid (p.Y277D), is pathogenic by 8 submitters. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PM5, PP3, PP4 LINK:https://erepo.genome.network/evrepo/ui/classification/CA229800/MONDO:0009861/006

Frequency

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

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

16

2

1

Clinical Significance

Pathogenic reviewed by expert panel P:3O:1

Conservation

PhyloP100: 6.24

Publications

6 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 10 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.

PM5

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.830A>G	p.Tyr277Cys	missense_variant	Exon 7 of 13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2 link	c.830A>G	p.Tyr277Cys	missense_variant	Exon 8 of 14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6 link	c.830A>G	p.Tyr277Cys	missense_variant	Exon 7 of 13	1	NM_000277.3	ENSP00000448059.1
PAH	ENST00000307000.7 link	c.815A>G	p.Tyr272Cys	missense_variant	Exon 8 of 14	5		ENSP00000303500.2
PAH	ENST00000549247.6 link	n.589A>G		non_coding_transcript_exon_variant	Exon 1 of 6	2
PAH	ENST00000635477.1 link	c.-11A>G		upstream_gene_variant		5		ENSP00000489230.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

1

AN:

152120

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

GnomAD2 exomes

AF:

0.00000796

AC:

2

AN:

251346

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

4

AN:

1461760

Hom.:

0

Cov.:

31

AF XY:

0.00000275

AC XY:

2

AN XY:

727184

show subpopulations

African (AFR)

AF:

0.00

AC:

0

AN:

33470

American (AMR)

AF:

0.0000224

AC:

1

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

0

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

0

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

0

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

0

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

0

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000270

AC:

3

AN:

1111920

Other (OTH)

AF:

0.00

AC:

0

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

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

Exome 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

GnomAD4 genome

AF:

0.00000657

AC:

1

AN:

152120

Hom.:

0

Cov.:

32

AF XY:

0.00

AC XY:

0

AN XY:

74312

show subpopulations

African (AFR)

AF:

0.00

AC:

0

AN:

41414

American (AMR)

AF:

0.0000655

AC:

1

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

0

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

0

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

0

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

0

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

0

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

0

AN:

68028

Other (OTH)

AF:

0.00

AC:

0

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.00

Hom.:

0

ExAC

AF:

0.00000824

AC:

1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:3

Aug 16, 2016

Counsyl

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Jun 08, 2020

ClinGen PAH Variant Curation Expert Panel

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

The c.830A>G (p.Tyr277Cys) variant in PAH has been reported in multiple individuals with PKU (PMID:24350308). This variant has an extremely low allele frequency (MAF=0.00006) in gnomAD. It was detected with multiple pathogenic variants: p.R408W in 2 patients; p.L194P (PMID: 24350308); c.842+1G>A in 2 patients (PMID: 25952249). Computational prediction tools and conservation analysis support a deleterious effect. Another missense change at the same amino acid (p.Y277D), is pathogenic by 8 submitters. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PM5, PP3, PP4 -

Aug 31, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant disrupts the p.Tyr277 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 2035532, 8268925, 8632937, 12173030, 12655546). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. 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. This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 277 of the PAH protein (p.Tyr277Cys). This variant is present in population databases (rs62516155, gnomAD 0.006%). This missense change has been observed in individuals with phenylketonuria (PMID: 32668217). ClinVar contains an entry for this variant (Variation ID: 102860). -

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

0.72

BayesDel_addAF

Pathogenic

0.44

D

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

28

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

1.0

D;D

Eigen

Pathogenic

0.77

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.97

D

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Pathogenic

0.70

D

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

0.94

D

MutationAssessor

Pathogenic

4.8

H;.

PhyloP100

6.2

PrimateAI

Pathogenic

0.86

D

PROVEAN

Pathogenic

-8.6

D;D

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;.

Vest4

0.91

MutPred

0.93

Loss of phosphorylation at Y277 (P = 0.0319);.;

MVP

0.99

MPC

0.26

ClinPred

1.0

D

GERP RS

4.6

PromoterAI

-0.033

Neutral

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.93

gMVP

0.98

Mutation Taster

=3/97

disease causing (ClinVar)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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: rs62516155; hg19: chr12-103246605; API