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NM_000277.3(PAH):c.204A>T (p.Arg68Ser) AND PAH-related disorder

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Oct 12, 2023
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV003398669.4

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:
PAH-related disorder
Synonyms:
PAH-related condition
Identifiers:

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004105331PreventionGenetics, part of Exact Sciences
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(Oct 12, 2023) 		germlineclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

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; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From PreventionGenetics, part of Exact Sciences, SCV004105331.1

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

Description

The PAH c.204A>T variant is predicted to result in the amino acid substitution p.Arg68Ser. This variant has been reported in the homozygous state or with a second causative PAH variant in numerous patients, primarily in those with mild phenylketonuria (mPKU) or non-PKU mild hyperphenylalaninemia (mHPA) (Rivera et al. 2011. PubMed ID: 21871829; Sarkissian et al. 2012. PubMed ID: 23430918; Quirk et al. 2012. PubMed ID: 22841515; Couce et al. 2013. PubMed ID: 23500595; Jeannesson-Thivisol et al. 2015. PubMed ID: 26666653). The p.Arg68Ser substitution has been reported to reduce PAH enzyme activity to a range of 18-76% of control activity, which would be consistent with mPKU or mHPA (Couce et al. 2013. PubMed ID: 23500595; Himmelreich et al. 2018. PubMed ID: 30037505). It is unclear whether the p.Arg68Ser substitution results in tetrahydrobiopterin (BH4) responsiveness (Quirk et al. 2012. PubMed ID: 22841515; Sarkissian et al. 2012. PubMed ID: 23430918). This variant is classified as a mild to moderate PKU variant in the PAH variant database database (http://www.biopku.org/pah/result-details-pah.asp?ID=707). It is classified as pathogenic by the ClinGen PAH Variant Curation Expert Panel and several other outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/92738/). In summary, we classify the c.204A>T (p.Arg68Ser) variant as pathogenic.

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

Last Updated: Oct 13, 2024