NM_000277.3(PAH):c.611A>G (p.Tyr204Cys) AND Phenylketonuria

Germline classification:: Pathogenic (8 submissions)
Last evaluated:: Mar 26, 2021
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000000621.96

Allele description [Variation Report for NM_000277.3(PAH):c.611A>G (p.Tyr204Cys)]

NM_000277.3(PAH):c.611A>G (p.Tyr204Cys)

Gene:

PAH:phenylalanine hydroxylase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

12q23.2

Genomic location:

Preferred name:

NM_000277.3(PAH):c.611A>G (p.Tyr204Cys)

HGVS:

NC_000012.12:g.102855231T>C
NG_008690.2:g.108180A>G
NM_000277.3:c.611A>GMANE SELECT
NM_001354304.2:c.611A>G
NP_000268.1:p.Tyr204Cys
NP_001341233.1:p.Tyr204Cys
NC_000012.11:g.103249009T>C
NM_000277.1:c.611A>G
P00439:p.Tyr204Cys

Protein change:

Y204C; TYR204CYS

Links:

UniProtKB: P00439#VAR_000924; OMIM: 612349.0013; dbSNP: rs62514927

NCBI 1000 Genomes Browser:

rs62514927

Molecular consequence:

NM_000277.3:c.611A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354304.2:c.611A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Phenylketonuria (PKU)
Synonyms:: Phenylketonurias; Oligophrenia phenylpyruvica; Folling disease
Identifiers:: MONDO: MONDO:0009861; MedGen: C0031485; Orphanet: 716; OMIM: 261600

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000020771	OMIM	no assertion criteria provided	Pathogenic (May 1, 1992)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000220596	Counsyl	no assertion criteria provided	Pathogenic (Oct 22, 2018)	unknown	clinical testing	PubMed (10) [See all records that cite these PMIDs] 8051931, 2071149, 8990021, 9048935, 15503242, 7844887, 23430918, 15793771, 19147918, 9949232
SCV000893948	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 31, 2018)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000917932	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Dec 13, 2018)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 8990021, 16256386, 26322415, 24401910 Citation Link,
SCV000950704	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 29, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 2589491, 15503242, 18985011, 8990021, 28492532
SCV001163722	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 12, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001453119	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV001572875	ClinGen PAH Variant Curation Expert Panel	reviewed by expert panel (ClinGen PAH ACMG Specifications v1)	Pathogenic (Mar 26, 2021)	germline	curation	Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

Identification of three novel PKU mutations among Chinese: evidence for recombination or recurrent mutation at the PAH locus.

Wang T, Okano Y, Eisensmith RC, Lo WH, Huang SZ, Zeng YT, Yuan LF, Liu SR, Woo SL.

Genomics. 1992 May;13(1):230-1.

PubMed [citation]

PMID:: 1349576

Molecular and population genetics of phenylketonuria in Orientals: correlation between phenotype and genotype.

Okano Y, Hase Y, Lee DH, Takada G, Shigematsu Y, Oura T, Isshiki G.

J Inherit Metab Dis. 1994;17(1):156-9. No abstract available.

PubMed [citation]

PMID:: 8051931

See all PubMed Citations (18)

PMC

Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL.

Genetics in medicine : official journal of the American College of Medical Genetics. 2015 Mar 5; 17(5): 405-424

PMC [article]

PMCID:: PMC4544753
PMID:: 25741868
DOI:: 10.1038/gim.2015.30

Details of each submission

From OMIM, SCV000020771.67

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

The tyr204-to-cys (Y204C) mutation, which occurs in exon 6 of PAH, was found on haplotype 4 in 12 (13%) of 81 alleles from Chinese patients with phenylketonuria (PKU; 261600) and 1 (5%) of 22 alleles from Japanese patients with PKU (Wang et al., 1991).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Counsyl, SCV000220596.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Fulgent Genetics, Fulgent Genetics, SCV000893948.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000917932.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Variant summary: PAH c.611A>G (p.Tyr204Cys) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Four predict the variant creates a 5' donor site. One publication reports experimental evidence showing that this variant affects mRNA splicing resulting in a 32-amino acid deletion in the core region of the PAH enzyme (Ellingsen_1997). The variant allele was found at a frequency of 1.2e-05 in 246108 control chromosomes (gnomAD). The variant, c.611A>G, has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (Tao_2015, Liang_2014, Song_2005, Ellingsen_1997). These data indicate that the variant is very likely to be associated with disease. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000950704.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 204 of the PAH protein (p.Tyr204Cys). RNA analysis indicates that this missense change induces altered splicing and likely results in the loss of 32 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs62514927, gnomAD 0.02%). This missense change has been observed in individual(s) with phenylketonuria (PMID: 2589491, 15503242, 18985011). 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: 590). 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%. Studies have shown that this missense change results in the activation of a cryptic splice site in exon 6 (PMID: 8990021). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV001163722.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV001453119.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ClinGen PAH Variant Curation Expert Panel, SCV001572875.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

The c.611A>G (p.Tyr204Cys) variant in PAH has been reported in multiple individuals with Classic PKU and MHP (BH4 deficiency excluded). (PMID: 15503242). This variant has a MAF (0.00016) in gnomAD. This variant creates a fully active, novel 5 Ì donor splice site which results in an aberrantly spliced mRNA with a 96-nt deletion at the 3 Ì-end of exon 6 PMID: 8990021 (aka Ex6-96A>G). Multiple lines of computational evidence support a deleterious effect. This variant was detected in trans with multiple pathogenic variants including: p.R111* (2); c.442-1G>A; p.R158W; p.L255S; p.P281L; p.K363Nfs*37; p.V399V; p.R408W; p.R241C (2); p.R243Q; p.R261Q (2); p.S349A; p.R413P; p.A434D (2) (PMID: 26322415). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4_Moderate, PM3_very-strong, PP3.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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