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NM_000277.3(PAH):c.618C>G (p.Tyr206Ter) AND Phenylketonuria

Germline classification:
Pathogenic (2 submissions)
Last evaluated:
Apr 13, 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:
RCV000578371.2

Allele description [Variation Report for NM_000277.3(PAH):c.618C>G (p.Tyr206Ter)]

NM_000277.3(PAH):c.618C>G (p.Tyr206Ter)

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.618C>G (p.Tyr206Ter)
HGVS:
  • NC_000012.12:g.102855224G>C
  • NG_008690.2:g.108187C>G
  • NM_000277.1(PAH):c.618C>G
  • NM_000277.3:c.618C>GMANE SELECT
  • NM_001354304.2:c.618C>G
  • NP_000268.1:p.Tyr206Ter
  • NP_001341233.1:p.Tyr206Ter
  • NC_000012.11:g.103249002G>C
  • NM_000277.1(PAH):c.618C>G
  • NM_000277.1:c.618C>G
  • p.Tyr206Ter
Protein change:
Y206*
Links:
dbSNP: rs62517201
NCBI 1000 Genomes Browser:
rs62517201
Molecular consequence:
  • NM_000277.3:c.618C>G - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001354304.2:c.618C>G - nonsense - [Sequence Ontology: SO:0001587]
Observations:
1

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

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000680450GeneID Lab - Advanced Molecular Diagnostics
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely pathogenic
(Sep 7, 2017) 		germlineclinical testing

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

SCV001370845ClinGen PAH Variant Curation Expert Panel
reviewed by expert panel

(ClinGen PAH ACMG Specifications v1)		Pathogenic
(Apr 13, 2020) 		germlinecuration

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

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration
Dutchgermlineno1not 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

Molecular epidemiology and genotype-phenotype correlation in phenylketonuria patients from South Spain.

Bueno MA, González-Lamuño D, Delgado-Pecellín C, Aldámiz-Echevarría L, Pérez B, Desviat LR, Couce ML.

J Hum Genet. 2013 May;58(5):279-84. doi: 10.1038/jhg.2013.16. Epub 2013 Mar 21.

PubMed [citation]
PMID:
23514811

Details of each submission

From GeneID Lab - Advanced Molecular Diagnostics, SCV000680450.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1Dutch1not providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenonot providednot providednot provided1not providednot providednot provided

From ClinGen PAH Variant Curation Expert Panel, SCV001370845.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (1)

Description

The c.618C>G (p.Tyr206Ter) variant in PAH is a null variant (nonsense variant) in exon 6 of 13 in a gene where LOF is a known mechanism of disease, leading to premature truncation and NMD (PVS1). It is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). It has been reported in at least six PKU patients (per abnormal blood Phe levels) (PP4), including in trans with pathogenic variants: with R158Q (pathogenic per PAH VCEP) (PMID: 30829006); homozygous in an Indian case with classic PKU (PMID: 24130151); in trans with the known pathogenic (per PAH VCEP) p.R408W variant (PMID: 9452062); in a Chinese PKU case in trans with the known pathogenic (per PAH VCEP) EX6-96A>G variant (PMID: 16256386); and in two Spanish patients, in trans with the pathogenic (per PAH VCEP) Thr380Met and the p.Ala309Val variants, respectively (PMID: 27121329) (PM3_VeryStrong). It has also been reported Likely Pathogenic by one lab in ClinVar (variation ID 102763). Classification: Pathogenic Supporting criteria: PVS1, PM2; PM3_VeryStrong; PP4

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

Last Updated: Apr 23, 2022