rs62516141

Positions:

chr12-102843688-T-C

Variant summary

Our verdict is Pathogenic. Variant got 7 ACMG points: 7P and 0B. PP3PM3PM2PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The c.1157A>G (p.Tyr386Cys) variant in PAH has been reported in multiple probands with PKU (BH4 deficiency excluded) (PMID:16198137; PP4_Moderate). This variant has been detected with c.1315+1G>A, R252W, L311P, R261Q, I65V, Q178G, R158Q (all reported as Pathogenic in ClinVar, 4.0 points total) (PMIDs:24368688, 24941924, 22841515, 16198137, 26210745, 23357515, 18493213; PM3_very-strong). This variant is absent from population databases (PM2) and is predicted deleterious by SIFT, PolyPhen2, MutationTaster, and REVEL = 0.975 (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PM2, PP4_Moderate, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA274152/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000068 ( 0 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:11O:1

Conservation

PhyloP100: 8.02

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 7 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.1157A>G	p.Tyr386Cys	missense_variant	11/13	ENST00000553106.6	NP_000268.1	P00439A0A024RBG4
PAH	NM_001354304.2 link	c.1157A>G	p.Tyr386Cys	missense_variant	12/14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6 link	c.1157A>G	p.Tyr386Cys	missense_variant	11/13	1	NM_000277.3	ENSP00000448059.1		P00439

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152066

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251290

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135802

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:

0.0000677

AC:

AN:

1461616

Hom.:

Cov.:

AF XY:

0.0000619

AC XY:

AN XY:

727108

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:

0.0000881

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152066

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74298

show subpopulations

Gnomad4 AFR

AF:

0.0000483

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000718

Hom.:

Bravo

AF:

0.0000151

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

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:6

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 10, 2023	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 386 of the PAH protein (p.Tyr386Cys). This variant is present in population databases (rs62516141, gnomAD 0.004%). This missense change has been observed in individual(s) with phenylketonuria or hyperphenylalaninemia (PMID: 16198137, 16765994, 22841515, 23430918, 24350308, 24368688). ClinVar contains an entry for this variant (Variation ID: 102538). 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. This variant disrupts the p.Tyr386 amino acid residue in PAH. Other variant(s) that disrupt this residue have been observed in individuals with PAH-related conditions (PMID: 23430918), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	May 15, 2021	The c.1157A>G (p.Tyr386Cys) variant in PAH has been reported in multiple probands with PKU (BH4 deficiency excluded) (PMID: 16198137; PP4_Moderate). This variant has been detected with c.1315+1G>A, R252W, L311P, R261Q, I65V, Q178G, R158Q (all reported as Pathogenic in ClinVar, 4.0 points total) (PMIDs:24368688, 24941924, 22841515, 16198137, 26210745, 23357515, 18493213; PM3_very-strong). This variant is absent from population databases (PM2) and is predicted deleterious by SIFT, PolyPhen2, MutationTaster, and REVEL = 0.975 (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PM2, PP4_Moderate, PP3. -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Aug 22, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 26, 2018	Variant summary: PAH c.1157A>G (p.Tyr386Cys) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain (IPR019774) 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 2e-05 in 246044 control chromosomes (gnomAD). c.1157A>G has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria)(Bayat_2016, Trunzo_2015, Ho_2014). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 14, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 13, 2023	- -

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	Quest Diagnostics Nichols Institute San Juan Capistrano	May 10, 2024	The PAH c.1157A>G (p.Tyr386Cys) variant has been reported in the published literature in multiple individuals affected with phenylketonuria (PKU) (PMID: 8533759 (1995), 10394930 (1999), 11385716 (2001), 12655553 (2003), 16198137 (2005), 16765994 (2006), 18493213 (2008), 22841515 (2012), 23357515 (2013), 23430918 (2012), 24350308 (2013), 24368688 (2014), 24941924 (2015), 26210745 (2015), 34828281 (2021), 36537053 (2022)). The frequency of this variant in the general population, 0.000044 (5/113648 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 16, 2024	Reported previously in association with hyperphenylalaninemia and seen in patients with classic PKU in the presence of another pathogenic variant (PMID: 8533759, 26210745, 24941924); Not observed at 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: 24941924, 24350308, 16765994, 22841515, 17924342, 29499199, 25087612, 11385716, 23357515, 11696894, 8533759, 24368688, 23430918, 12655553, 23074961, 10394930, 9634518, 18493213, 16198137, 32668217, 35405047, 36646061, 36537053, 21445337, 34828281, 26210745) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 03, 2023	PP3, PM2_moderate, PM3_very_strong, PS4_moderate -

PAH-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 19, 2024

The PAH c.1157A>G variant is predicted to result in the amino acid substitution p.Tyr386Cys. This variant has been reported, in the homozygous state or with a second causative PAH variant, in multiple individuals with phenylalanine hydroxylase deficiency (e.g., Fiori et al. 2005. PubMed ID: 16198137; Lüleyap et al. 2006. PubMed ID: 16765994; Quirk et al. 2012. PubMed ID: 22841515; Sarkissian et al. 2012. PubMed ID: 23430918; Table S3, Hillert et al. 2020. PubMed ID: 32668217). We have also observed this variant in presumably affected individuals that also carried a second pathogenic or likely pathogenic variant in PAH (PreventionGenetics internal data). This variant is interpreted as pathogenic by the ClinGen PAH Variant Curation Expert Panel, and as likely pathogenic or pathogenic by other submitters to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/102538). This variant is reported in 0.0044% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Based on the collective evidence, we classify this variant as pathogenic. -

Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Undiagnosed Diseases Network, NIH

Oct 27, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

1.0

D;D

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Pathogenic

0.78

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

0.90

MutationAssessor

Pathogenic

4.8

H;.

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-8.5

D;D

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.98

MVP

1.0

MPC

0.26

ClinPred

1.0

GERP RS

5.3

Varity_R

0.97

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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