rs62517164

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP4PP3

This summary comes from the ClinGen Evidence Repository: The c.811C>T (p.His271Tyr) variant in PAH has been reported in 2 unrelated PKU patients. BH4 deficiencies not assessed. (PMID:9012412) A deleterious effect is predicted in SIFT, Polyphen2, MutationTaster, and REVEL=0.978. This variant has an extremely low frequency in ExAC, 1000G, ESP, and gnomAD (MAF=0.00001). . In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP3, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229784/MONDO:0009861/006

Frequency

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

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:1U:4O:1

Conservation

PhyloP100: 10.0

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 Uncertain_significance. Variant got 4 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.811C>T	p.His271Tyr	missense_variant	Exon 7 of 13	ENST00000553106.6	NP_000268.1	P00439A0A024RBG4
PAH	NM_001354304.2 link	c.811C>T	p.His271Tyr	missense_variant	Exon 8 of 14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PAH	ENST00000553106.6 link	c.811C>T	p.His271Tyr	missense_variant	Exon 7 of 13	1	NM_000277.3	ENSP00000448059.1	P00439
PAH	ENST00000307000.7 link	c.796C>T	p.His266Tyr	missense_variant	Exon 8 of 14	5		ENSP00000303500.2	J3KND8
PAH	ENST00000549247.6 link	n.570C>T		non_coding_transcript_exon_variant	Exon 1 of 6	2
PAH	ENST00000635477.1 link	c.-30C>T		upstream_gene_variant		5		ENSP00000489230.1	A0A0U1RQY4

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152154

Hom.:

Cov.:

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251344

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135834

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 SAS 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:

0.00000616

AC:

AN:

1461832

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727220

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:

0.00000540

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000478

Hom.:

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:4Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:1Uncertain:2

Dec 10, 2018

ClinGen PAH Variant Curation Expert Panel

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The c.811C>T (p.His271Tyr) variant in PAH has been reported in 2 unrelated PKU patients. BH4 deficiencies not assessed. (PMID: 9012412) A deleterious effect is predicted in SIFT, Polyphen2, MutationTaster, and REVEL=0.978. This variant has an extremely low frequency in ExAC, 1000G, ESP, and gnomAD (MAF=0.00001). . In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP3, PP4. -

Sep 15, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.His271 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18299955). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This variant is not present in population databases (gnomAD no frequency). 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. ClinVar contains an entry for this variant (Variation ID: 102849). This missense change has been observed in individual(s) with phenylketonuria (PMID: 9012412). This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 271 of the PAH protein (p.His271Tyr). -

Oct 16, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Uncertain:1Other:1

DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jan 10, 2020

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Identified in two unrelated individuals with PKU, however a second variant not described in either patient (Tyfield et al., 1997); This variant is associated with the following publications: (PMID: 9012412, 25087612) -

See cases

Uncertain:1

Dec 08, 2021

Institute of Human Genetics, University Hospital Muenster

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG categories: PM1,PM2,PP3,BP1 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

1.0

D;D

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Pathogenic

0.61

MetaRNN

Pathogenic

0.96

D;D

MetaSVM

Pathogenic

0.97

MutationAssessor

Pathogenic

4.1

H;.

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-5.8

D;D

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;.

Vest4

0.89

MVP

0.99

MPC

0.25

ClinPred

1.0

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.96

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over