12-102843688-T-C

Variant names:

• chr12-102843688-T-C
• rs62516141
• NM_000277.3:c.1157A>G

Variant summary

Our verdict is Pathogenic. The variant received 7 ACMG points: 7P and 0B. PP3 PM3 PM2 PP4_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
• Clinical Significance: Pathogenic reviewed by expert panel P:11 O:1
• Conservation: PhyloP100: 8.02
• Publications: 15 publications found

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 Gene-Disease associations (from GenCC):

• phenylketonuria

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Myriad Women’s Health
• classic phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• maternal phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mild hyperphenylalaninemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mild phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• tetrahydrobiopterin-responsive hyperphenylalaninemia/phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000277.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAH	NM_000277.3	MANE Select	c.1157A>G	p.Tyr386Cys	missense	Exon 11 of 13	NP_000268.1
	PAH	NM_001354304.2		c.1157A>G	p.Tyr386Cys	missense	Exon 12 of 14	NP_001341233.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAH	ENST00000553106.6	TSL:1 MANE Select	c.1157A>G	p.Tyr386Cys	missense	Exon 11 of 13	ENSP00000448059.1
	PAH	ENST00000307000.7	TSL:5	c.1142A>G	p.Tyr381Cys	missense	Exon 12 of 14	ENSP00000303500.2
	PAH	ENST00000635477.1	TSL:5	c.260A>G	p.Tyr87Cys	missense	Exon 4 of 6	ENSP00000489230.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152066 Hom.: 0 Cov.: 31

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

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251290 AF XY: 0.0000368

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000677 AC: 99 AN: 1461616 Hom.: 0 Cov.: 30 AF XY: 0.0000619 AC XY: 45 AN XY: 727108

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000881 AC: 98 AN: 1111820

Other (OTH) AF: 0.0000166 AC: 1 AN: 60382

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152066 Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3 AN XY: 74298

African (AFR) AF: 0.0000483 AC: 2 AN: 41394

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000549 Hom.: 0

Bravo AF: 0.0000151

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:6

Dec 13, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 12, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PAH protein function with a positive predictive value of 80%. 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.

Oct 14, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Aug 22, 2014

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Oct 26, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

May 15, 2021

ClinGen PAH Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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.

not provided Pathogenic:3 Other:1

Jun 17, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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)

DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Nov 03, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, PM2_moderate, PM3_very_strong, PS4_moderate

May 10, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

PAH-related disorder Pathogenic:1

Aug 19, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Oct 27, 2022

Undiagnosed Diseases Network, NIH

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	1.0	D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	4.8	H
PhyloP100		8.0
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-8.5	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MVP		1.0
MPC		0.26
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.97
gMVP		0.98
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs62516141; hg19: chr12-103237466;