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NM_000277.3(PAH):c.157C>T (p.Arg53Cys) AND Phenylketonuria

Germline classification:
Likely pathogenic (4 submissions)
Last evaluated:
May 29, 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:
RCV000664566.9

Allele description [Variation Report for NM_000277.3(PAH):c.157C>T (p.Arg53Cys)]

NM_000277.3(PAH):c.157C>T (p.Arg53Cys)

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.157C>T (p.Arg53Cys)
HGVS:
  • NC_000012.12:g.102912802G>A
  • NG_008690.2:g.50609C>T
  • NM_000277.3:c.157C>TMANE SELECT
  • NM_001354304.2:c.157C>T
  • NP_000268.1:p.Arg53Cys
  • NP_001341233.1:p.Arg53Cys
  • NC_000012.11:g.103306580G>A
  • NC_000012.11:g.103306580G>A
  • NM_000277.1:c.157C>T
  • NM_000277.3(PAH):c.157C>TMANE SELECT
  • p.Arg53Cys
Protein change:
R53C
Links:
dbSNP: rs199475619
NCBI 1000 Genomes Browser:
rs199475619
Molecular consequence:
  • NM_000277.3:c.157C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354304.2:c.157C>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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000788553Counsyl
criteria provided, single submitter

(Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))
Uncertain significance
(Dec 28, 2017)
unknownclinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link,

SCV001762319ClinGen PAH Variant Curation Expert Panel
reviewed by expert panel

(ClinGen PAH ACMG Specifications v1)
Likely pathogenic
(May 29, 2021)
germlinecuration

Citation Link,

SCV002317207Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Jan 8, 2024)
germlineclinical testing

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

SCV003816614Revvity Omics, Revvity
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Jun 28, 2023)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

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

Citations

PubMed

Predicted effects of missense mutations on native-state stability account for phenotypic outcome in phenylketonuria, a paradigm of misfolding diseases.

Pey AL, Stricher F, Serrano L, Martinez A.

Am J Hum Genet. 2007 Nov;81(5):1006-24. Epub 2007 Oct 2.

PubMed [citation]
PMID:
17924342
PMCID:
PMC2265664

Spectrum of PAH gene variants among a population of Han Chinese patients with phenylketonuria from northern China.

Liu N, Huang Q, Li Q, Zhao D, Li X, Cui L, Bai Y, Feng Y, Kong X.

BMC Med Genet. 2017 Oct 5;18(1):108. doi: 10.1186/s12881-017-0467-7. Erratum in: BMC Med Genet. 2018 Jan 9;19(1):6. doi: 10.1186/s12881-017-0516-2.

PubMed [citation]
PMID:
28982351
PMCID:
PMC5629770
See all PubMed Citations (4)

Details of each submission

From Counsyl, SCV000788553.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From ClinGen PAH Variant Curation Expert Panel, SCV001762319.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

This c.157C>T (p.Arg53Cys) variant in PAH was reported in trans with pathogenic variant p.Arg158Gln in 1 patient with PAH deficiency (324 uMol/L Phe) (PMID: 28982351). This variant was found at an amino acid residue where p.Arg53His, a missense variant of uncertain significance, has been seen before. Computational evidence for this missense variant supports a deleterious effect (REVEL=0.766). This variant is found at an extremely low frequency in gnomAD and ExAC (MAF=0.00012), and absent from 1000 Genomes, and ESP. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP3, PP4.

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002317207.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 53 of the PAH protein (p.Arg53Cys). This variant is present in population databases (rs199475619, gnomAD 0.01%). This missense change has been observed in individual(s) with phenylketonuria (PMID: 28982351; Invitae). 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: 102600). 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%. For these reasons, this variant has been classified as Pathogenic.

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

From Revvity Omics, Revvity, SCV003816614.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 13, 2024