NM_000277.3(PAH):c.977G>A (p.Trp326Ter) AND Phenylketonuria

Germline classification:: Pathogenic (5 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:: RCV000000609.82

Allele description [Variation Report for NM_000277.3(PAH):c.977G>A (p.Trp326Ter)]

NM_000277.3(PAH):c.977G>A (p.Trp326Ter)

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.977G>A (p.Trp326Ter)

HGVS:

NC_000012.12:g.102844424C>T
NG_008690.2:g.118987G>A
NM_000277.3:c.977G>AMANE SELECT
NM_001354304.2:c.977G>A
NP_000268.1:p.Trp326Ter
NP_001341233.1:p.Trp326Ter
NC_000012.11:g.103238202C>T
NM_000277.1:c.977G>A
NM_000277.2(PAH):c.977G>A
p.Trp326Ter

Protein change:

W326*; TRP326TER

Links:

OMIM: 612349.0015; dbSNP: rs62514959

NCBI 1000 Genomes Browser:

rs62514959

Molecular consequence:

NM_000277.3:c.977G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001354304.2:c.977G>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
SCV000020759	OMIM	no assertion criteria provided	Pathogenic (Nov 1, 1989)	germline	literature only	PubMed (1) [See all records that cite this PMID] Wang, T., Woo, S. L. C. Personal Communication. 1990. Houston, Tex.,
SCV000799431	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Pathogenic (Apr 20, 2018)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 23764561, 23932990, 28982351 Citation Link,
SCV001370856	ClinGen PAH Variant Curation Expert Panel	reviewed by expert panel (ClinGen PAH ACMG Specifications v1)	Pathogenic (Apr 13, 2020)	germline	curation	PubMed (2) [See all records that cite these PMIDs] 24705691, 25456745 Citation Link,
SCV001586285	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Mar 29, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 29499199, 1301187, 9634518, 28492532
SCV004209654	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 17, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

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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
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Molecular genetics of phenylketonuria in Orientals: linkage disequilibrium between a termination mutation and haplotype 4 of the phenylalanine hydroxylase gene.

Wang T, Okano Y, Eisensmith R, Huang SZ, Zeng YT, Lo WH, Woo SL.

Am J Hum Genet. 1989 Nov;45(5):675-80.

PubMed [citation]

PMID:: 2816939
PMCID:: PMC1683443

Phenylalanine hydroxylase deficiency in the Slovak population: genotype-phenotype correlations and genotype-based predictions of BH4-responsiveness.

Polak E, Ficek A, Radvanszky J, Soltysova A, Urge O, Cmelova E, Kantarska D, Kadasi L.

Gene. 2013 Sep 10;526(2):347-55. doi: 10.1016/j.gene.2013.05.057. Epub 2013 Jun 10.

PubMed [citation]

PMID:: 23764561

See all PubMed Citations (11)

Details of each submission

From OMIM, SCV000020759.67

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

The trp326-to-ter (W326X) mutation in exon 10 of PAH was found on haplotype 4 in a Chinese patient with phenylketonuria (PKU; 261600) (Wang and Woo, 1990). Also see Wang et al. (1992).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Counsyl, SCV000799431.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

#	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, SCV001370856.1

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

Description

The c.977G>A (p.Trp326Ter) is a variant in PAH is a null variant (nonsense variant) in a gene where LOF is a known mechanism of disease, leading to premature truncation and NMD (PVS1). It is present at extremely low frequencies in ethnically diverse control databases (gnomAD AF 0.00000399; PAH PM2 cutoff: <0.0002) (PM2). It has been identified in at least five PKU cases in whom BH4 deficiency was excluded (PP4_Moderate), in four cases in trans with known pathogenic variants (PM3_VeryStrong). It has been identified in at least two Chinese classic PKU cases (PMID: 261600; PMID: 1301927; PMID: 28982351), in trans with the known pathogenic (per PAH VCEP) p.Y356X and p.R243Q variants; as a single heterozygous variant in a Chinese classic PKU case with BH4 deficiency excluded (PMID: 24705691); in trans with the known pathogenic (per PAH VCEP) p.R261Q variant in one Slovak case with classic PKU with BH4 deficiency said to be excluded (PMID: 23764561); one Chinese proband with mild hyperphenylalanemia in trans with c.1197A>T (p.V399V) (PMID: 25456745). It is also listed Pathogenic in ClinVar by three labs (variant ID 579). Classification: Pathogenic Supporting Criteria: PVS1, PM2; PM3_VeryStrong; PP4_Moderate

#	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, SCV001586285.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with hyperphenylalaninemia (PMID: 29499199). ClinVar contains an entry for this variant (Variation ID: 579). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Trp326*) 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).

#	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, SCV004209654.1

#	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

Last Updated: May 1, 2024

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