12-102855313-C-G

Position:

chr12-102855313-C-G

Variant summary

Our verdict is Pathogenic. Variant got 6 ACMG points: 6P and 0B. PM3PM2PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The c.529G>C (p.Val177Leu) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded). (PP4_Moderate). This variant has an extremely low allele frequency (Pop Max MAF=0.00005 ENF) in gnomAD (PM2). This variant was detected with pathogenic variants: F39L, L48S, F39del, R408W, R261Q, F55fs, R158Q, Trp187*. Parental testing not reported. PMID:8659548, PMID:16879198, PMID:19609714, PMID:23430918, PMID:22391997, PMID:22513348, PMID:26666653 (PM3_very-strong. Computational prediction tools and conservation analysis do not agree. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM3_very-strong, PM2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229610/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:10O:1

Conservation

PhyloP100: 3.39

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.

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.529G>C	p.Val177Leu	missense_variant	6/13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2 linkuse as main transcript	c.529G>C	p.Val177Leu	missense_variant	7/14		NP_001341233.1
PAH	XM_017019370.2 linkuse as main transcript	c.529G>C	p.Val177Leu	missense_variant	6/7		XP_016874859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
PAH	ENST00000553106.6 linkuse as main transcript	c.529G>C	p.Val177Leu	missense_variant	6/13	1	NM_000277.3	ENSP00000448059	P1
PAH	ENST00000549111.5 linkuse as main transcript	n.625G>C		non_coding_transcript_exon_variant	6/6	1
PAH	ENST00000307000.7 linkuse as main transcript	c.514G>C	p.Val172Leu	missense_variant	7/14	5		ENSP00000303500
PAH	ENST00000551988.5 linkuse as main transcript	n.550G>C		non_coding_transcript_exon_variant	5/5	3

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152142

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251188

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135756

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:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461830

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727224

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:

0.0000108

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74316

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:7

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 12, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Oct 02, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 14, 2018	Variant summary: PAH c.529G>C (p.Val177Leu) results in a conservative amino acid change located in the catalytic domain of the encoded protein sequence (Jeannesson-Thivisol 2015). Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.9e-05 in 276898 control chromosomes. This frequency is not higher than expected for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (2.9e-05 vs 0.0079), allowing no conclusion about variant significance. The variant, c.529G>C has been reported in the literature in multiple individuals affected with mild Phenylalanine Hydroxylase Deficiency (Phenylketonuria) and also found in individuals with Hyperphenylalaninemia (e.g. Djordjevic 2012, Sterl 2013, Reblova 2013, Anjema 2013, Jeannesson-Thivisol2015). These data indicate that the variant is very likely to be associated with disease. Tetrahydrobiopterin (BH4) responsiveness was reported to be inconsistent in patients, probably influenced by the other variant found in trans (Djordjevic 2012, Anjema 2013). In a recent study a compound heterozygous patient carrying this mutation with a null mutation, was found to be BH4-responsive (Jeannesson-Thivisol 2015). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 30, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	Oct 25, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 177 of the PAH protein (p.Val177Leu). This variant is present in population databases (rs199475602, gnomAD 0.006%). This missense change has been observed in individual(s) with PAH-related conditions (PMID: 8659548, 8807331, 22513348, 23430547, 24789341, 25087612, 26666653). ClinVar contains an entry for this variant (Variation ID: 102727). 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.Val177 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12501224, 17096675, 23430547, 23500595, 23764561, 27121329). 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. -
Pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Sep 22, 2019	The c.529G>C (p.Val177Leu) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded). (PP4_Moderate). This variant has an extremely low allele frequency (Pop Max MAF=0.00005 ENF) in gnomAD (PM2). This variant was detected with pathogenic variants: F39L, L48S, F39del, R408W, R261Q, F55fs, R158Q, Trp187*. Parental testing not reported. PMID: 8659548, PMID: 16879198, PMID: 19609714, PMID: 23430918, PMID: 22391997, PMID: 22513348, PMID: 26666653 (PM3_very-strong. Computational prediction tools and conservation analysis do not agree. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM3_very-strong, PM2. -

not provided

Pathogenic:2Other:1

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 31, 2018	The V177L variant in the PAH gene has been reported as a pathogenic variant in the PAH Consortium database. The V177L variant has previously been reported in association with mild phenylketonuria (PKU) and hyperphenylalaninemia (Eiken et al., 1996; RÃ©blovÃ¡ et al.,2013; Jeannesson-Thivisol et al., 2015). Tetrahydrobiopterin (BH4) responsiveness is inconsistent in patients with V177L (Zurfluh et al., 2008; Sarkissian et al., 2012; Anjema et al., 2013). Therefore, we interpret V177L in PAH as a pathogenic variant. -
not provided, no classification provided	literature only	DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	-	- -

PAH-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 10, 2022

The PAH c.529G>C variant is predicted to result in the amino acid substitution p.Val177Leu. This patient is also heterozygous in the PAH gene for a sequence variant designated c.529G>C, which is predicted to result in the amino acid substitution p.Val177Leu. This variant has been reported, along with a second pathogenic PAH variant, in several individuals that presented with either mild hyperphenylalaninemia (MHP) or mild phenylketonuria (mPKU) (Guldberg et al. 1996. PubMed ID: 8659548; Langenbeck et al. 2009. PubMed ID: 19609714; Feillet et al. 2014. PubMed ID: 24789341; Djordjevic et al. 2013. PubMed ID: 23430547). Different substitutions of the same codon (p.Val177Met, p.Val177Ala) have also been reported in association with phenylalanine hydroxylase deficiency (Muntau et al. 2002. PubMed ID: 12501224; Jennings et al. 2000. PubMed ID: 10980574). Internally, we have observed the c.529G>C (p.Val177Leu) variant along with a second pathogenic PAH variant in affected individuals. This variant is also documented in the PAH variant database (http://www.biopku.org/home/home.asp) and is classified as a MHP variant. Additionally, it is interpreted as pathogenic by the ClinGen PAH Variant Curation Expert Panel and as pathogenic or likely pathogenic by other outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/102727/). Based on the collective evidence, this variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.28

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.96

D;D

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

D;D

M_CAP

Pathogenic

0.45

MetaRNN

Pathogenic

0.94

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.2

M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-2.4

N;N

REVEL

Pathogenic

0.78

Sift

Uncertain

0.0050

D;D

Sift4G

Uncertain

0.021

D;D

Polyphen

0.048

B;.

Vest4

0.88

MutPred

0.95

Loss of sheet (P = 0.1158);.;

MVP

0.97

MPC

0.045

ClinPred

0.70

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.86

gMVP

0.91

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