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

Clinical significance:Pathogenic (Last evaluated: Jul 24, 2020)

Review status:3 stars out of maximum of 4 stars

reviewed by expert panel

Based on:
5 submissions [Details]
Record status:
current
Accession:
RCV000150091.14

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_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

Recent activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000220635Counsylcriteria provided, single submitter
Likely pathogenic
(Aug 26, 2014)
unknownliterature only

PubMed (21)
[See all records that cite these PMIDs]

Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015),

Citation Link,

SCV000629187Invitaecriteria provided, single submitter
Pathogenic
(Oct 30, 2020)
germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV000696443Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Sep 9, 2016)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

LabCorp Variant Classification Summary - May 2015.docx,

Citation Link,

SCV001448287ClinGen PAH Variant Curation Expert Panelreviewed by expert panel
Pathogenic
(Jul 24, 2020)
germlinecuration

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV001455115Natera, Inc.no assertion criteria providedPathogenic
(Sep 16, 2020)
germlineclinical testing

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing, curation
not providedunknownunknownnot providednot providednot providednot providednot providedliterature only

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 (27)

Details of each submission

From Counsyl, SCV000220635.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (21)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV000629187.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

This sequence change replaces arginine with serine at codon 68 of the PAH protein (p.Arg68Ser). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and serine. This variant is present in population databases (rs76394784, ExAC 0.007%). This variant has been described as a prevalent Galician variant (PMID: 23500595). It has been reported as compound heterozygous in multiple individuals affected with mild and classic phenylketonuria (PKU) (PMID: 9634518, 11051201, 23500595, 23764561, 23514811). ClinVar contains an entry for this variant (Variation ID: 92738). Experimental studies have shown that this missense change decreases the stability of the PAH protein (PMID: 21953985). For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000696443.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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."

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From ClinGen PAH Variant Curation Expert Panel, SCV001448287.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Natera, Inc., SCV001455115.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 12, 2021

Support Center