NM_000277.3(PAH):c.398_401del (p.Asn133fs) AND Phenylketonuria

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Oct 14, 2022
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:: RCV000531628.10

Allele description [Variation Report for NM_000277.3(PAH):c.398_401del (p.Asn133fs)]

NM_000277.3(PAH):c.398_401del (p.Asn133fs)

Gene:

PAH:phenylalanine hydroxylase [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

12q23.2

Genomic location:

Preferred name:

NM_000277.3(PAH):c.398_401del (p.Asn133fs)

Other names:

NM_000277.3(PAH):c.398_401del; p.Asn133fs

HGVS:

NC_000012.12:g.102877504_102877507del
NG_008690.2:g.85906_85909del
NM_000277.3:c.398_401delMANE SELECT
NM_001354304.2:c.398_401del
NP_000268.1:p.Asn133fs
NP_001341233.1:p.Asn133fs
NC_000012.11:g.103271280_103271283del
NC_000012.11:g.103271282_103271285del
NM_000277.1:c.398_401del
NM_000277.1:c.398_401delATCA

Protein change:

N133fs

Links:

dbSNP: rs199475605

NCBI 1000 Genomes Browser:

rs199475605

Molecular consequence:

NM_000277.3:c.398_401del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354304.2:c.398_401del - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV000629191	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 1, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 1301187, 9634518, 10429004, 23430918, 26666653, 28492532
SCV000788569	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Pathogenic (Jan 24, 2017)	unknown	clinical testing	PubMed (4) [See all records that cite these PMIDs] 22513348, 8659548, 26666653, 22526846 Citation Link,
SCV002600846	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Oct 31, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 8659548, 22513348 Citation Link,
SCV002818522	ClinGen PAH Variant Curation Expert Panel	reviewed by expert panel (ClinGen PAH ACMG Specifications v1)	Pathogenic (Oct 14, 2022)	germline	curation	Citation Link,
SCV004201367	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 16, 2023)	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

Citations

PubMed

Molecular basis of phenylketonuria and related hyperphenylalaninemias: mutations and polymorphisms in the human phenylalanine hydroxylase gene.

Eisensmith RC, Woo SL.

Hum Mutat. 1992;1(1):13-23. Review.

PubMed [citation]

PMID:: 1301187

A European multicenter study of phenylalanine hydroxylase deficiency: classification of 105 mutations and a general system for genotype-based prediction of metabolic phenotype.

Guldberg P, Rey F, Zschocke J, Romano V, François B, Michiels L, Ullrich K, Hoffmann GF, Burgard P, Schmidt H, Meli C, Riva E, Dianzani I, Ponzone A, Rey J, Güttler F.

Am J Hum Genet. 1998 Jul;63(1):71-9. Erratum in: Am J Hum Genet 1998 Oct;63(4):1252-3.

PubMed [citation]

PMID:: 9634518
PMCID:: PMC1377241

See all PubMed Citations (10)

Details of each submission

From Invitae, SCV000629191.7

#	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.Asn133Argfs*61) 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 individual(s) with phenylketonuria (PKU) (PMID: 10429004, 23430918, 26666653). ClinVar contains an entry for this variant (Variation ID: 102663). 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 Counsyl, SCV000788569.1

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

#	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, SCV002600846.1

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

Description

Variant summary: PAH c.398_401delATCA (p.Asn133ArgfsX61) 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 251466 control chromosomes (gnomAD). c.398_401delATCA has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (e.g. Guldberg_1996, Groselj_2012). These data indicate that the variant is very likely to be associated with disease. Three ClinVar submitters (evaluation after 2014) cite 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 ClinGen PAH Variant Curation Expert Panel, SCV002818522.1

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

Description

This c.398_401del (p.Asn133fs) variant in PAH was detected with pathogenic and likely pathogenic variants in multiple patients with classic PKU and one with mild hyperphenylalaninemia (PMID: 22513348, 22526846, 8659548, 22917871, 26666653). This variant was absent in population databases. This is a frameshift variant in exon 4 of 13 predicted to undergo nonsense mediated decay. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3_Strong, 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 Baylor Genetics, SCV004201367.1

#	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: Feb 14, 2024

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