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NM_000277.3(PAH):c.2T>G (p.Met1Arg) AND Phenylketonuria

Germline classification:
Pathogenic (1 submission)
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:
RCV000993612.1

Allele description [Variation Report for NM_000277.3(PAH):c.2T>G (p.Met1Arg)]

NM_000277.3(PAH):c.2T>G (p.Met1Arg)

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>G (p.Met1Arg)
HGVS:
  • NC_000012.12:g.102917129A>C
  • NG_008690.2:g.46282T>G
  • NM_000277.3:c.2T>GMANE SELECT
  • NM_001354304.2:c.2T>G
  • NP_000268.1:p.Met1Arg
  • NP_001341233.1:p.Met1Arg
  • NC_000012.11:g.103310907A>C
  • NM_000277.1:c.2T>G
  • NM_000277.2(PAH):c.2T>G
  • p.Met1Arg
Protein change:
M1R
Links:
dbSNP: rs62508575
NCBI 1000 Genomes Browser:
rs62508575
Molecular consequence:
  • NM_000277.3:c.2T>G - initiator_codon_variant - [Sequence Ontology: SO:0001582]
  • NM_001354304.2:c.2T>G - initiator_codon_variant - [Sequence Ontology: SO:0001582]
  • NM_000277.3:c.2T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354304.2:c.2T>G - 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

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001146720ClinGen PAH Variant Curation Expert Panel
reviewed by expert panel

(ClinGen PAH ACMG Specifications v1)		Pathogenic
(Jul 7, 2019) 		germlinecuration

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

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Citations

PubMed

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

Details of each submission

From ClinGen PAH Variant Curation Expert Panel, SCV001146720.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (1)

Description

The PAH:p.M1R variant is a predicted start-lost variant in the canonical transcript of PAH (ENST00000553106). 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. The variant has been previously reported in 2 unrelated probands with classic PKU, in trans with the pathogenic variant p.R408W (PMID: 10679941; PM3); BH4 deficiency was excluded (PP4_Moderate). The variant is sufficiently rare in control databases (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3, PM2, PP4_moderate, PVS1.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 3, 2023