rs140175796

Positions:

chr12-102877469-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PP3PM3_StrongPM2PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The c.434A>T (p.Asp145Val) PAH variant has been identified in patients with PAH deficiency from the US, Germany, Italy and Spain. BH4 deficiency was excluded. (PMID:8659548; 11385716; 12655553; 17096675; 23514811) It was detected with known pathogenic variants: V388M (PMID:8659548), I65T (PMID:24368688), and R408W (PMID:26666653). It is found at extremely low frequency (MAF 0.00012 in gnomAD). A deleterious effect is predicted in SIFT, Polyphen2, MutationTaster, and REVEL=0.987. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PP4_Moderate, PP3 LINK:https://erepo.genome.network/evrepo/ui/classification/CA229539/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.000086 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000085 ( 0 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:11O:1

Conservation

PhyloP100: 7.38

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 Likely_pathogenic. Variant got 9 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 link	c.434A>T	p.Asp145Val	missense_variant	4/13	ENST00000553106.6	NP_000268.1	P00439A0A024RBG4
PAH	NM_001354304.2 link	c.434A>T	p.Asp145Val	missense_variant	5/14		NP_001341233.1
PAH	XM_017019370.2 link	c.434A>T	p.Asp145Val	missense_variant	4/7		XP_016874859.1
LOC124902999	XR_007063428.1 link	n.808-2410T>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6 link	c.434A>T	p.Asp145Val	missense_variant	4/13	1	NM_000277.3	ENSP00000448059.1		P00439

Frequencies

GnomAD3 genomes

AF:

0.0000856

AC:

AN:

151878

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.000162

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.0000636

AC:

AN:

251484

Hom.:

AF XY:

0.0000662

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000967

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000849

AC:

124

AN:

1461042

Hom.:

Cov.:

AF XY:

0.0000880

AC XY:

AN XY:

726896

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000936

Gnomad4 NFE exome

AF:

0.0000963

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000856

AC:

AN:

151878

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

74164

show subpopulations

Gnomad4 AFR

AF:

0.0000242

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:

0.000162

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.000135

Hom.:

Bravo

AF:

0.0000831

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:11Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:7

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Apr 14, 2017	- -
Likely pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Dec 10, 2018	The c.434A>T (p.Asp145Val) PAH variant has been identified in patients with PAH deficiency from the US, Germany, Italy and Spain. BH4 deficiency was excluded. (PMID: 8659548; 11385716; 12655553; 17096675; 23514811) It was detected with known pathogenic variants: V388M (PMID: 8659548), I65T (PMID: 24368688), and R408W (PMID: 26666653). It is found at extremely low frequency (MAF 0.00012 in gnomAD). A deleterious effect is predicted in SIFT, Polyphen2, MutationTaster, and REVEL=0.987. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PP4_Moderate, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 27, 2023	Variant summary: PAH c.434A>T (p.Asp145Val) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 251484 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (6.4e-05 vs 0.0079), allowing no conclusion about variant significance. c.434A>T has been reported in the literature in several affected individuals with biochemically confirmed mild form of HPA or PKU, and was predicted to be BH4-responsive allele. The following publications have been ascertained in the context of this evaluation (PMID: 25087612, 24368688, 8659548, 26666653, 17096675, 27121329, 10541324). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Dec 11, 2018	The PAH c.434A>T (p.Asp145Val) missense variant has been reported in seven studies in which it is found in a total of seven individuals in a compound heterozygous state, and in one in a heterozygous state with no second variant detected (Guldberg et al. 1996, Mallolas et al. 1999, Yang et al. 2001, Aulehla-Scholz et al. 2003, Dahri et al. 2010, Ho et al. 2013, Jeannesson-Thivisol et al. 2015). Individuals with the p.Asp145Val variant were described as having mild hyperphenylalaninemia. The p.Asp145Val variant was absent from 620 healthy controls (Aulehla-Scholz et al. 2003, Ho et al. 2014) and is reported at a frequency of 0.00006 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence, the p.Asp145Val variant is classified as pathogenic for phenylalanine hydroxylase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 27, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 30, 2023	This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 145 of the PAH protein (p.Asp145Val). This variant is present in population databases (rs140175796, gnomAD 0.01%). This missense change has been observed in individual(s) with phenylalanine levels >180 umol/L findings that are highly specific for hyperphenylalaninemia (PMID: 8659548, 26666653). ClinVar contains an entry for this variant (Variation ID: 102667). 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%. Experimental studies have shown that this missense change affects PAH function (PMID: 27121329). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:2Other:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 17, 2023	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26666653, 11180595, 24368688, 32778825, 10394930, 11678552, 10598814, 10527663, 31747680, 25087612, 27469133, 10429004, 17096675, 19786003, 11385716, 12655553, 14654663, 10541324, 31589614, 23514811, 27121329, 33465300, 32668217, 8659548) -
not provided, no classification provided	literature only	DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 08, 2021	PP3, PP4_moderate, PM3_very_strong, PM5, PS3 -

PAH-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 08, 2023

The PAH c.434A>T variant is predicted to result in the amino acid substitution p.Asp145Val. This variant has previously been reported, along with a second known pathogenic PAH variant, in patients with phenylalanine hydroxylase deficiency (for example, see Guldberg et al. 1996. PubMed ID: 8659548; Aulehla-Scholz and Heilbronner, 2003. PubMed ID: 12655553; Hillert et al. 2020. PubMed ID: 32668217). It has been reported that the p.Asp145Val amino acid substitution may result in a PAH protein that is somewhat responsive to tetrahydrobiopterin (BH4), although this has not been clearly established (Ho et al. 2014. PubMed ID: 24368688; Jeannesson-Thivisol et al. 2015. PubMed ID: 26666653). Several other laboratories classify this variant as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/102667/), and the ClinGen PAH Variant Curation Expert Panel classifies it as likely pathogenic (Zastrow et al. 2018. PubMed ID: 30311390). This variant is reported in 0.011% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-103271247-T-A). In summary, the c.434A>T (p.Asp145Val) variant is interpreted as likely pathogenic. -

See cases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Sep 09, 2020

ACMG classification criteria: PS4, PM2, PM3, PP3, PP4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.67

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.99

D;D

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.87

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

0.95

MutationAssessor

Pathogenic

4.3

H;.

PrimateAI

Uncertain

0.79

PROVEAN

Pathogenic

-8.4

D;D

REVEL

Pathogenic

0.99

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.96

MVP

0.98

MPC

0.27

ClinPred

1.0

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.91

gMVP

0.94

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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