NM_000277.3(PAH):c.58C>T (p.Gln20Ter) AND Phenylketonuria

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Feb 26, 2019
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:: RCV000169450.13

Allele description [Variation Report for NM_000277.3(PAH):c.58C>T (p.Gln20Ter)]

NM_000277.3(PAH):c.58C>T (p.Gln20Ter)

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.58C>T (p.Gln20Ter)

HGVS:

NC_000012.12:g.102917073G>A
NG_008690.2:g.46338C>T
NM_000277.3:c.58C>TMANE SELECT
NM_001354304.2:c.58C>T
NP_000268.1:p.Gln20Ter
NP_001341233.1:p.Gln20Ter
NC_000012.11:g.103310851G>A
NM_000277.1:c.58C>T
NM_000277.2(PAH):c.58C>T
p.Gln20Ter

Protein change:

Q20*

Links:

dbSNP: rs199475585

NCBI 1000 Genomes Browser:

rs199475585

Molecular consequence:

NM_000277.3:c.58C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354304.2:c.58C>T - 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
SCV000220871	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Nov 12, 2014)	unknown	literature only	PubMed (8) [See all records that cite these PMIDs] 23764561, 22841515, 16879198, 9284280, 9634518, 23357515, 9391881, 23430547 Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015), Citation Link,
SCV001146739	ClinGen PAH Variant Curation Expert Panel	reviewed by expert panel (ClinGen PAH ACMG Specifications v1)	Pathogenic (Feb 26, 2019)	germline	curation	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001370580	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (May 25, 2020)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 22841515, 23764561, 23357515, 9634518, 23430547, 9391881 Citation Link,
SCV001400667	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 15, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 1301187, 9634518, 9391881, 23357515, 23430547, 23764561, 27121329, 28492532
SCV005053825	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 21, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

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, literature only

Citations

PubMed

Molecular and phenotypic characteristics of patients with phenylketonuria in Serbia and Montenegro.

Stojiljkovic M, Jovanovic J, Djordjevic M, Grkovic S, Cvorkov Drazic M, Petrucev B, Tosic N, Karan Djurasevic T, Stojanov L, Pavlovic S.

Clin Genet. 2006 Aug;70(2):151-5.

PubMed [citation]

PMID:: 16879198

Intellectual, neurologic, and neuropsychologic outcome in untreated subjects with nonphenylketonuria hyperphenylalaninemia. German Collaborative Study on Phenylketonuria.

Weglage J, Ullrich K, Pietsch M, Fünders B, Güttler F, Harms E.

Pediatr Res. 1997 Sep;42(3):378-84.

PubMed [citation]

PMID:: 9284280

See all PubMed Citations (12)

Details of each submission

From Counsyl, SCV000220871.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (8)

#	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, SCV001146739.1

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

Description

Pathogenic: The c.58C>T (p.Gln20Ter) is a null variant reported in one patient with classic PKU phenotype (PVS1, PP4, PMID: 9391881). This variant is absent from population databases, including gnomAD, 1000 Genomes, and ESP (PM2). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, 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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001370580.1

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

Description

Variant summary: PAH c.58C>T (p.Gln20X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the 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. The variant was absent in 251430 control chromosomes. c.58C>T has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (example, Kozak_1997, Guldberg_1998, Quirk_2012, Djordjevic_2013, Polak_2013, Reblova_2013). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory and one expert panel (ClinGen) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was 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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001400667.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This sequence change creates a premature translational stop signal (p.Gln20*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with phenylketonuria (PKU) (PMID: 9391881, 23357515, 23430547, 23764561, 27121329). ClinVar contains an entry for this variant (Variation ID: 102744). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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 Baylor Genetics, SCV005053825.1

#	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: Oct 20, 2024

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