rs752792040

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2_SupportingPM3_SupportingPP3_ModeratePP4

This summary comes from the ClinGen Evidence Repository: The c.307G>T (p.Gly103Cys) variant in PAH has been reported in 2 patients with PKU (BH4 deficiency not assessed/reported) (PP4; PMID:17502162, 24368688). It was detected in unknown phase with a pathogenic variant c.1066-11G>A (PMID:17502162) and a likely pathogenic variant p.Y154F (PMID:24368688). This variant has extremely low frequency in ExAC (MAF=0.00001). Computational evidence supports a deleterious effect (REVEL=0.819). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2_supporting, PM3_supporting, PP3_moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA6748984/MONDO:0009861/006

Frequency

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

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.84

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:

LOC124902999 (HGNC:):

LOC124902999 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 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.

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/exons	MANE	Protein
PAH	NM_000277.3 linkuse as main transcript	c.307G>T	p.Gly103Cys	missense_variant	3/13	ENST00000553106.6	NP_000268.1
LOC124902999	XR_007063428.1 linkuse as main transcript	n.863-9918C>A		intron_variant, non_coding_transcript_variant
PAH	NM_001354304.2 linkuse as main transcript	c.307G>T	p.Gly103Cys	missense_variant	4/14		NP_001341233.1
PAH	XM_017019370.2 linkuse as main transcript	c.307G>T	p.Gly103Cys	missense_variant	3/7		XP_016874859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6 linkuse as main transcript	c.307G>T	p.Gly103Cys	missense_variant	3/13	1	NM_000277.3	ENSP00000448059	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152098

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

GnomAD4 exome

AF:

0.00000752

AC:

AN:

1461850

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727222

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:

0.00000989

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152098

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74296

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

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:1Uncertain:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 12, 2023	This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 103 of the PAH protein (p.Gly103Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hyperphenylalaninemia (PMID: 17502162, 24368688, 32668217; Invitae). ClinVar contains an entry for this variant (Variation ID: 553638). 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 not expected to disrupt PAH protein function with a negative predictive value of 80%. This variant disrupts the p.Gly103 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 31355225). 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. -
Uncertain significance, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Jul 23, 2023	The c.307G>T (p.Gly103Cys) variant in PAH has been reported in 2 patients with PKU (BH4 deficiency not assessed/reported) (PP4; PMID: 17502162, 24368688). It was detected in unknown phase with a pathogenic variant c.1066-11G>A (PMID: 17502162) and a likely pathogenic variant p.Y154F (PMID: 24368688). This variant has extremely low frequency in ExAC (MAF=0.00001). Computational evidence supports a deleterious effect (REVEL=0.819). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2_supporting, PM3_supporting, PP3_moderate. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Sep 01, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Jan 30, 2024	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

May 21, 2024

Variant summary: PAH c.307G>T (p.Gly103Cys) results in a non-conservative amino acid change located in the ACT domain (IPR002912) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.307G>T has been reported in the literature in compound heterozygous individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (e.g. Dobrowolski_2007, Ho_2014). 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: 17502162, 32668217, 24368688). ClinVar contains an entry for this variant (Variation ID: 553638). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.22

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.35

T;T;T;T

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.89

D;D;D;D

M_CAP

Uncertain

0.28

MetaRNN

Pathogenic

0.74

D;D;D;D

MetaSVM

Pathogenic

0.97

MutationAssessor

Benign

0.98

L;.;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.44

N;N;N;N

REVEL

Pathogenic

0.82

Sift

Benign

0.077

T;T;T;T

Sift4G

Benign

0.14

T;T;T;.

Polyphen

0.98

D;.;.;.

Vest4

0.87

MutPred

0.39

Loss of disorder (P = 0.0488);.;Loss of disorder (P = 0.0488);Loss of disorder (P = 0.0488);

MVP

0.99

MPC

0.16

ClinPred

0.88

GERP RS

6.2

Varity_R

0.39

gMVP

0.75

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

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