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

Germline classification:: Pathogenic (6 submissions)
Last evaluated:: Oct 13, 2023
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:: RCV000672692.12

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

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

Other names:

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

HGVS:

NC_000012.12:g.102855224G>T
NG_008690.2:g.108187C>A
NM_000277.3:c.618C>AMANE SELECT
NM_001354304.2:c.618C>A
NP_000268.1:p.Tyr206Ter
NP_001341233.1:p.Tyr206Ter
NC_000012.11:g.103249002G>T
NM_000277.1:c.618C>A

Protein change:

Y206*

Links:

dbSNP: rs62517201

NCBI 1000 Genomes Browser:

rs62517201

Molecular consequence:

NM_000277.3:c.618C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354304.2:c.618C>A - nonsense - [Sequence Ontology: SO:0001587]

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000797826	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Pathogenic (Feb 13, 2018)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 24130151, 25456745 Citation Link,
SCV000919907	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Sep 8, 2017)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 16256386, 10527663, 11139255, 26503515, 24130151 Citation Link,
SCV000946663	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 22, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 1301187, 9634518, 16256386, 24130151, 27121329, 28492532
SCV001453118	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV004209586	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 6, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004222619	ClinGen PAH Variant Curation Expert Panel	reviewed by expert panel (ClinGen PAH ACMG Specifications v1)	Pathogenic (Oct 13, 2023)	germline	curation	Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Fast clinical molecular diagnosis of hyperphenylalaninemia using next-generation sequencing-based on a custom AmpliSeq™ panel and Ion Torrent PGM sequencing.

Cao YY, Qu YJ, Song F, Zhang T, Bai JL, Jin YW, Wang H.

Mol Genet Metab. 2014 Dec;113(4):261-6. doi: 10.1016/j.ymgme.2014.10.004. Epub 2014 Oct 12.

PubMed [citation]

PMID:: 25456745

The structural basis of phenylketonuria.

Erlandsen H, Stevens RC.

Mol Genet Metab. 1999 Oct;68(2):103-25. Review.

PubMed [citation]

PMID:: 10527663

See all PubMed Citations (11)

Details of each submission

From Counsyl, SCV000797826.1

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

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000919907.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

Variant summary: The PAH c.618C>A (p.Tyr206X) variant results in a premature termination codon, predicted to cause a truncated or absent PAH protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.727C>T, p.Arg243X; c.1055delG, p.Gly352fsX48; c.1089delG, p.Lys363fsX37). One in silico tool predicts a damaging outcome for this variant. One functional study confirmed that the variant leads to a nonsense mutation that caused significant reduction in mutant transcript levels possibly through activation of nonsense mediated decay (Bashyam 2014). This variant was found in 1/121330 control chromosomes at a frequency of 0.00082%, which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.79057%). The variant was reported in the literature in multiple patients with PKU (Song 2006, Bashyam 2014, Li 2015, Acosta 2001). Taken together, this variant is 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 Invitae, SCV000946663.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change creates a premature translational stop signal (p.Tyr206*) in the PAH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518). This variant is present in population databases (rs62517201, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with phenylketonuria (PMID: 16256386, 24130151, 27121329). ClinVar contains an entry for this variant (Variation ID: 556660). 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 Natera, Inc., SCV001453118.1

#	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 Baylor Genetics, SCV004209586.2

#	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

From ClinGen PAH Variant Curation Expert Panel, SCV004222619.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

The c.618C>A (p.Tyr206Ter) is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 6/13 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. It has been detected in 4 patients with classic PKU with known pathogenic variants: c.611A>G (PMID: 16256386); p.Arg241Cys (PMID:25456745); and c.1197A>T p.Val399Val (PMID: 30050108). This variant has extremely low frequency in gnomAD (MAF=0.00005). In summary, this variant meets criteria to be classified as Pathogenic for PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH VCEP: PM2_supporting, PM3_strong, PP4, PVS1.

#	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

Last Updated: Jun 17, 2024

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