NM_000277.3(PAH):c.2T>C (p.Met1Thr) AND Phenylketonuria

Germline classification:: Likely pathogenic (5 submissions)
Last evaluated:: Jul 7, 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:: RCV000984289.10

Allele description [Variation Report for NM_000277.3(PAH):c.2T>C (p.Met1Thr)]

NM_000277.3(PAH):c.2T>C (p.Met1Thr)

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.2T>C (p.Met1Thr)

Other names:

p.M1T:ATG>ACG

HGVS:

NC_000012.12:g.102917129A>G
NG_008690.2:g.46282T>C
NM_000277.3:c.2T>CMANE SELECT
NM_001354304.2:c.2T>C
NP_000268.1:p.Met1Thr
NP_001341233.1:p.Met1Thr
NC_000012.11:g.103310907A>G
NM_000277.1(PAH):c.2T>C
NM_000277.1:c.2T>C
p.Met1Thr

Protein change:

M1T

Links:

dbSNP: rs62508575

NCBI 1000 Genomes Browser:

rs62508575

Molecular consequence:

NM_000277.3:c.2T>C - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_001354304.2:c.2T>C - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_000277.3:c.2T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354304.2:c.2T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Phenylketonuria (PKU)
Synonyms:: Phenylketonurias; Oligophrenia phenylpyruvica; Folling disease
Identifiers:: MONDO: MONDO:0009861; MedGen: C0031485; Orphanet: 716; OMIM: 261600

Recent activity

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Homo sapiens CD164 sialomucin-like 2, mRNA (cDNA clone MGC:169089 IMAGE:9021466)...
Homo sapiens CD164 sialomucin-like 2, mRNA (cDNA clone MGC:169089 IMAGE:9021466), complete cds
gi|187952274|gb|BC137466.1|

Nucleotide
TCAAP1D8292 Pediatric acute myelogenous leukemia cell (FAB M1) Baylor-HGSC proje...
TCAAP1D8292 Pediatric acute myelogenous leukemia cell (FAB M1) Baylor-HGSC project=TCAA Homo sapiens cDNA clone TCAAP8292, mRNA sequence
gi|17164358|gnl|dbEST|10421177|gb|B 10.1|

Nucleotide
CHPF2 [Ailuropoda melanoleuca]
CHPF2 [Ailuropoda melanoleuca]
Gene ID:100481231

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001132447	Counsyl	no assertion criteria provided	Likely pathogenic (Jul 2, 2014)	unknown	clinical testing
SCV001146696	ClinGen PAH Variant Curation Expert Panel	reviewed by expert panel (ClinGen PAH ACMG Specifications v1)	Likely pathogenic (Jul 7, 2019)	germline	curation	Citation Link,
SCV001383680	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 12, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 2574002, 10679941, 24941924, 26666653, 28492532
SCV002088682	Natera, Inc.	no assertion criteria provided	Pathogenic (Feb 27, 2021)	germline	clinical testing
SCV002811022	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 11, 2021)	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

Citations

PubMed

Novel PKU mutation on haplotype 2 in French-Canadians.

John SW, Rozen R, Laframboise R, Laberge C, Scriver CR.

Am J Hum Genet. 1989 Dec;45(6):905-9.

PubMed [citation]

PMID:: 2574002
PMCID:: PMC1683463

Phenylketonuria and hyperphenylalaninemia in eastern Germany: a characteristic molecular profile and 15 novel mutations.

Hennermann JB, Vetter B, Wolf C, Windt E, Bührdel P, Seidel J, Mönch E, Kulozik AE.

Hum Mutat. 2000;15(3):254-60.

PubMed [citation]

PMID:: 10679941

See all PubMed Citations (6)

Details of each submission

From Counsyl, SCV001132447.2

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ClinGen PAH Variant Curation Expert Panel, SCV001146696.2

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

Description

c.2T>C (p.Met1Thr) is a null PAH variant (start loss) where LOF is a known mechanism of disease. There are no known alternative start codons in other transcripts. The next in-frame Met is at amino acid 180 in exon 6. There are 49 pathogenic variants in ClinVar upstream of aa 180. The p.Met1Val variant has <3% enzyme activity as compared to wild type (PMID: 9450897), confirming start loss variants lead to loss of function of the PAH enzyme without re-initiation. This variant has an extremely low frequency in ExAC, ESP, gnomAD. However, it has not been reported in the literature to our knowledge. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2.

#	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, SCV001383680.6

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

Description

This sequence change affects the initiator methionine of the PAH mRNA. The next in-frame methionine is located at codon 180. This variant is present in population databases (rs62508575, gnomAD 0.01%). Disruption of the initiator codon has been observed in individuals with hyperphenylalaninemia (PMID: 2574002, 10679941, 24941924, 26666653; Invitae). ClinVar contains an entry for this variant (Variation ID: 203873). 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., SCV002088682.2

#	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 Fulgent Genetics, Fulgent Genetics, SCV002811022.2

#	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

Last Updated: Feb 20, 2024

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