rs62516062

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 6 ACMG points: 6P and 0B. PM3PP3PP4PM2

This summary comes from the ClinGen Evidence Repository: The c.1033G>T (p.Ala345Ser) variant in PAH has been reported in multiple individuals with PAH deficiency. (PMID:24368688, 17502162, 3430918). This variant has an extremely low allele frequency (MAF=0.00008) in gnomAD. It was detected with multiple pathogenic variants: p.R408W (in trans, PMID:24368688); c.1045T>C, c.194T>C (PMID:17502162); p.F39del, c.47_48delCT (aka c.43_44CT), c.1066-11G>A (PMID:23430918); p.E280K, p.L348V, p.Y414C (PMID:31623983). Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_VS, PM2, PP3, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA286497/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:11O:1

Conservation

PhyloP100: 7.91

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 Pathogenic. Variant got 6 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	UniProt
PAH	NM_000277.3 linkuse as main transcript	c.1033G>T	p.Ala345Ser	missense_variant	10/13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2 linkuse as main transcript	c.1033G>T	p.Ala345Ser	missense_variant	11/14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6 linkuse as main transcript	c.1033G>T	p.Ala345Ser	missense_variant	10/13	1	NM_000277.3	ENSP00000448059	P1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152188

Hom.:

Cov.:

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

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251238

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135774

show subpopulations

Gnomad AFR exome

AF:

0.000123

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000301

AC:

AN:

1461418

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

727038

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

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:

0.0000360

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000354

Hom.:

Bravo

AF:

0.0000151

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:7

Pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Jun 05, 2020	The c.1033G>T (p.Ala345Ser) variant in PAH has been reported in multiple individuals with PAH deficiency. (PMID: 24368688, 17502162, 3430918). This variant has an extremely low allele frequency (MAF=0.00008) in gnomAD. It was detected with multiple pathogenic variants: p.R408W (in trans, PMID: 24368688); c.1045T>C, c.194T>C (PMID: 17502162); p.F39del, c.47_48delCT (aka c.43_44CT), c.1066-11G>A (PMID: 23430918); p.E280K, p.L348V, p.Y414C (PMID: 31623983). Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_VS, PM2, PP3, PP4. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 01, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jan 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 30, 2017	Variant summary: The PAH c.1033G>T (p.Ala345Ser) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution. The variant lies within the C-terminal aromatic amino acid hydroxylase domain (InterPro) and 4/5 in silico tools predict a damaging outcome for this variant. This variant was found in the large control database ExAC at a frequency of 0.0000166 (2/120330 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.0079057). Published studies have identified the variant in numerous with patients with PKU and/or HPA, including reports of this variant in compound heterozygosity with other pathogenic/likely pathogenic variants and evidence that the variant cosegregates with disease in a family (Ho_JIMDReports_2013). Additionally, one publication that analyzed the crystal structure of PAH protein reported that the variant of interest is one of "three residues in the active site that are located near the (putative) location of substrate binding or in the region near the catalytic iron" sites, suggesting the variant likely disrupts the critical functions of the protein (Erlandsen_Pediatrics_2003). There are no published in vitro functional studies for the variant; however calculation of the energetic impact (G) by structural modeling shows that this variant leads to lower impact on PAH stability and predicted to cause mild hyperphenylalaninemia (Pey_2007). Multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 20, 2023	This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 345 of the PAH protein (p.Ala345Ser). This variant is present in population databases (rs62516062, gnomAD 0.008%). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 17502162, 23430918, 24368688). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 102484). 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 with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

not provided

Pathogenic:3Other:1

not provided, no classification provided	literature only	DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 04, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2024	Responsive to tetrahydrobiopterin (BH4) therapy is unclear (PMID: 23430918); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24368688, 25525159, 14654665, 3430918, 17502162, 31623983, 32778825, 32668217, 23430918) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 21, 2022	The frequency of this variant in the general population, 0.000023 (3/129068 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant is associated with a variable phenotype that ranges from non-PKU hyperphenylalaninemia to classic PKU (PMIDs: 32668217 (2020), 24368688 (2014), 23430918 (2012), 17502162 (2007), and 12173030 (2002)). In addition, this variant has been observed in individuals with reported PAH deficiency (PMID: 24368688 (2014) and 17502162 (2007)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. -

PAH-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 03, 2024

The PAH c.1033G>T variant is predicted to result in the amino acid substitution p.Ala345Ser. This variant has been reported in the compound heterozygous state in multiple unrelated patients with PAH-related disorders (Sarkissian et al. 2012. PubMed ID: 23430918; Ho et al. 2014. PubMed ID: 24368688). The patient reported by Ho and colleagues presented with non-PKU hyperphenylalaninemia. A different change to the same amino acid (c.1033G>A, p.Ala345Thr) has also been reported to be causative for phenylalanine hydroxylase deficiency (Eisensmith and Woo. 1992. PubMed ID: 1301187; Karacic et al. 2009. PubMed ID: 19394257). The c.1033G>T (p.Ala345Ser) variant has been interpreted as pathogenic by the ClinGen PAH Variant Curation Expert Panel, as well as multiple other laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/102484/). It is reported in 0.0080% of alleles in individuals of African descent in gnomAD. Based on the collective evidence, this variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.98

D;D

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.95

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Pathogenic

0.64

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

0.97

MutationAssessor

Pathogenic

3.6

H;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-2.9

D;D

REVEL

Pathogenic

0.96

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

1.0

D;.

Vest4

0.95

MutPred

0.96

Gain of disorder (P = 0.0198);.;

MVP

0.96

MPC

0.23

ClinPred

0.98

GERP RS

5.8

Varity_R

0.82

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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