NM_000277.3(PAH):c.1002C>A (p.Cys334Ter) AND Phenylketonuria

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Oct 15, 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:: RCV003476584.2

Allele description [Variation Report for NM_000277.3(PAH):c.1002C>A (p.Cys334Ter)]

NM_000277.3(PAH):c.1002C>A (p.Cys334Ter)

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.1002C>A (p.Cys334Ter)

Other names:

NM_001354304.2:c.1002C>A

HGVS:

NC_000012.12:g.102844399G>T
NG_008690.2:g.119012C>A
NM_000277.3:c.1002C>AMANE SELECT
NM_001354304.2:c.1002C>A
NP_000268.1:p.Cys334Ter
NP_001341233.1:p.Cys334Ter
NC_000012.11:g.103238177G>T

Protein change:

C334*

Molecular consequence:

NM_000277.3:c.1002C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354304.2:c.1002C>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
SCV004201356	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 19, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004222624	ClinGen PAH Variant Curation Expert Panel	reviewed by expert panel (ClinGen PAH ACMG Specifications v1)	Pathogenic (Oct 15, 2023)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004201356

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Oct 19, 2023)

unknown

clinical testing

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

SCV004222624

ClinGen PAH Variant Curation Expert Panel

reviewed by expert panel

(ClinGen PAH ACMG Specifications v1)

Pathogenic
(Oct 15, 2023)

germline

curation

Citation Link

Help

Summary from all submissions

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

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 Baylor Genetics, SCV004201356.1

#	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, SCV004222624.1

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

Description

The c.1002C>A (p.Cys334Ter) variant in PAH is a nonsense variant in exon 10 of 13 predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). It was reported in a PKU patient from Shaanxi with blood Phe concentration over 2.0 mg/dL (PMID: 24510568; PP4). This variant is absent from gnomAD. In summary, this variant meets the criteria to be classified as pathogenic for PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH VCEP: PVS1, PM2_supporting, PP4.

#	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: Jan 6, 2024

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