Variant rs62517163 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM3_StrongPM2PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The c.1114A>T (p.Thr372Ser) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded, PMID:8807319, 21147011, 30050108). This variant has an extremely low frequency in gnomAD (MAF=0.00001). This variant was detected with multiple pathogenic/likely pathogenic variants: p.R408W, c.1066-11G>A (PMID:21147011); p.A300S (PMID:8807319); p.P281L (2 patients, LP), delF39 (PMID:10947211). Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229350/MONDO:0009861/006

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:5O:1

Conservation

PhyloP100: 6.27

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 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.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAH	NM_000277.3 linkuse as main transcript	c.1114A>T	p.Thr372Ser	missense_variant	11/13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2 linkuse as main transcript	c.1114A>T	p.Thr372Ser	missense_variant	12/14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6 linkuse as main transcript	c.1114A>T	p.Thr372Ser	missense_variant	11/13	1	NM_000277.3	ENSP00000448059	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251312

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135810

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:

0.00000137

AC:

AN:

1461514

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727092

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	The PAH c.1114A>T (p.Thr372Ser) missense variant has been reported in three studies in which it is found in a total of six Turkish patients with hyperphenylalanemia, a milder form of phenylalanine hydroxylase deficiency, in a compound heterozygous state (van der Sijs-Bos et al. 1996; Yilmaz et al. 2000; Ãœnal et al. 2015). Control data are unavailable for this variant which is not found in the 1000 Genomes Project, the Exome Sequencing Project or the Exome Aggregation Consortium. Based on the evidence, the p.Thr372Ser variant is classified as likely pathogenic for phenylalanine hydroxylase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Likely pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Aug 14, 2020	The c.1114A>T (p.Thr372Ser) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded, PMID: 8807319, 21147011, 30050108). This variant has an extremely low frequency in gnomAD (MAF=0.00001). This variant was detected with multiple pathogenic/likely pathogenic variants: p.R408W, c.1066-11G>A (PMID: 21147011); p.A300S (PMID: 8807319); p.P281L (2 patients, LP), delF39 (PMID: 10947211). Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong. -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Aug 10, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 16, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 27, 2022	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. ClinVar contains an entry for this variant (Variation ID: 102528). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 8807319, 30747360, 32668217; BIOPKU http://www.biopku.org). This variant is present in population databases (rs62517163, gnomAD 0.0009%). This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 372 of the PAH protein (p.Thr372Ser). -

not provided

Other:1

not provided, no classification provided

literature only

DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.52

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.98

D;D

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.82

T;T

M_CAP

Pathogenic

0.68

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.1

H;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-3.3

D;D

REVEL

Pathogenic

0.91

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

0.15

B;.

Vest4

0.85

MutPred

0.88

Gain of disorder (P = 0.0655);.;

MVP

0.99

MPC

0.086

ClinPred

0.99

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.92

gMVP

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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