NM_000277.3(PAH):c.204A>T (p.Arg68Ser) AND Phenylketonuria

Germline classification:: Pathogenic (7 submissions)
Last evaluated:: Jul 24, 2020
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:: RCV000150091.35

Allele description [Variation Report for NM_000277.3(PAH):c.204A>T (p.Arg68Ser)]

NM_000277.3(PAH):c.204A>T (p.Arg68Ser)

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.204A>T (p.Arg68Ser)

HGVS:

NC_000012.12:g.102894883T>A
NG_008690.2:g.68528A>T
NM_000277.3:c.204A>TMANE SELECT
NM_001354304.2:c.204A>T
NP_000268.1:p.Arg68Ser
NP_000268.1:p.Arg68Ser
NP_001341233.1:p.Arg68Ser
NC_000012.11:g.103288661T>A
NM_000277.1:c.204A>T
P00439:p.Arg68Ser

Protein change:

R68S

Links:

UniProtKB: P00439#VAR_000885; dbSNP: rs76394784

NCBI 1000 Genomes Browser:

rs76394784

Molecular consequence:

NM_000277.3:c.204A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354304.2:c.204A>T - 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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Homo sapiens phosphodiesterase 4B, cAMP-specific (phosphodiesterase E4 dunce hom...
Homo sapiens phosphodiesterase 4B, cAMP-specific (phosphodiesterase E4 dunce homolog, Drosophila), mRNA (cDNA clone IMAGE:4393859)
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Homo sapiens cDNA clone IMAGE:5262278, containing frame-shift errors
Homo sapiens cDNA clone IMAGE:5262278, containing frame-shift errors
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000220635	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Aug 26, 2014)	unknown	literature only	PubMed (21) [See all records that cite these PMIDs] 15557004, 22841515, 9634518, 11524738, 23500595, 16143554, 10495930, 11326337, 24350308, 8889590, 17513426, 12655553, 19609714, 21871829, 23074961, 10693064, 11678552, 17935162, 23430918, 10394930, 15464430 Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015), Citation Link,
SCV000629187	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 17, 2024)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 9634518, 11051201, 23500595, 23514811, 23764561, 21953985, 28492532
SCV000696443	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Sep 9, 2016)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 23500595, 23764561, 26666653 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV001448287	ClinGen PAH Variant Curation Expert Panel	reviewed by expert panel (ClinGen PAH ACMG Specifications v1)	Pathogenic (Jul 24, 2020)	germline	curation	PubMed (2) [See all records that cite these PMIDs] 26666653, 23764561 Citation Link,
SCV001455115	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV002016493	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 20, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004201324	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 23, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

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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, literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

Correction of kinetic and stability defects by tetrahydrobiopterin in phenylketonuria patients with certain phenylalanine hydroxylase mutations.

Erlandsen H, Pey AL, Gámez A, Pérez B, Desviat LR, Aguado C, Koch R, Surendran S, Tyring S, Matalon R, Scriver CR, Ugarte M, Martínez A, Stevens RC.

Proc Natl Acad Sci U S A. 2004 Nov 30;101(48):16903-8. Epub 2004 Nov 19.

PubMed [citation]

PMID:: 15557004
PMCID:: PMC534739

Utility of phenylalanine hydroxylase genotype for tetrahydrobiopterin responsiveness classification in patients with phenylketonuria.

Quirk ME, Dobrowolski SF, Nelson BE, Coffee B, Singh RH.

Mol Genet Metab. 2012 Sep;107(1-2):31-6. doi: 10.1016/j.ymgme.2012.07.008. Epub 2012 Jul 20.

PubMed [citation]

PMID:: 22841515
PMCID:: PMC4029439

See all PubMed Citations (28)

Details of each submission

From Counsyl, SCV000220635.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (21)

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000629187.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 68 of the PAH protein (p.Arg68Ser). This variant is present in population databases (rs76394784, gnomAD 0.01%). This missense change has been observed in individual(s) with mild and classic phenylketonuria (PKU) (PMID: 9634518, 11051201, 23500595, 23514811, 23764561). ClinVar contains an entry for this variant (Variation ID: 92738). 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%. Experimental studies have shown that this missense change affects PAH function (PMID: 21953985). 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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000696443.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: The PAH c.204A>T (p.Arg68Ser) variant causes a missense change involving a non-conserved nucleotide with 5/5 in silico tools predicting a damaging outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 5/121282 (1/24271), which does not exceed the estimated maximal expected allele frequency for a pathogenic PAH variant of 1/126. Multiple publications cite the variant in affected compound heterozygote and homozygote individuals. In addition, multiple reputable databases and clinical diagnostic laboratories cite the variant as "likely pathogenic/pathogenic." Therefore, the variant of interest has been classified as a "Pathogenic Variant."

#	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, SCV001448287.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (2)

Description

The c.204A>T (p.Arg68Ser) variant in PAH was reported in a Spanish patient with mild/moderate PKU. A defect in the synthesis or regeneration pathways 6R-BH4 was ruled out by analyzing urinary pterin levels and by measuring the dihydropteridine reductase activity (PMID 27121329). It was detected in trans with several pathogenic variants including p.Ala300Ser, p.Asp415Asn, p.Arg158Gln, and c.1315+1G>A (PMID 27121329, 22841515). This variant was found in low frequency in gnomAD (MAF=0.00016) and was predicted deleterious using in silico data. 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, and 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

From Natera, Inc., SCV001455115.1

#	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 Revvity Omics, Revvity, SCV002016493.3

#	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	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004201324.2

#	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

Last Updated: Oct 13, 2024

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