NM_000277.3(PAH):c.836C>T (p.Pro279Leu) AND Phenylketonuria

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Dec 12, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000190377.7

Allele description [Variation Report for NM_000277.3(PAH):c.836C>T (p.Pro279Leu)]

NM_000277.3(PAH):c.836C>T (p.Pro279Leu)

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.836C>T (p.Pro279Leu)

HGVS:

NC_000012.12:g.102852821G>A
NG_008690.2:g.110590C>T
NM_000277.3:c.836C>TMANE SELECT
NM_001354304.2:c.836C>T
NP_000268.1:p.Pro279Leu
NP_001341233.1:p.Pro279Leu
NC_000012.11:g.103246599G>A
NM_000277.1:c.836C>T

Protein change:

P279L

Links:

dbSNP: rs796064503

NCBI 1000 Genomes Browser:

rs796064503

Molecular consequence:

NM_000277.3:c.836C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354304.2:c.836C>T - 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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LOC107661440 [Sinocyclocheilus anshuiensis]
LOC107661440 [Sinocyclocheilus anshuiensis]
Gene ID:107661440

Gene
LOC103741264 [Nannospalax galili]
LOC103741264 [Nannospalax galili]
Gene ID:103741264

Gene
LAG3 lymphocyte activating 3 [Homo sapiens]
LAG3 lymphocyte activating 3 [Homo sapiens]
Gene ID:3902

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000243911	Inserm U 954, Faculté de Médecine de Nancy	no assertion criteria provided	probable-pathogenic	unknown	not provided
SCV003934427	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (May 16, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 32668217, 21890392, 25551302 Citation Link,
SCV004209633	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 22, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004294281	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 12, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 21890392, 32668217, 28492532
SCV004848714	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 30, 2022)	germline	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
not provided	not provided	not provided	not provided	not provided	not provided	1	not provided	not provided
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Plasma cholesterol in adults with phenylketonuria.

Williams RA, Hooper AJ, Bell DA, Mamotte CD, Burnett JR.

Pathology. 2015 Feb;47(2):134-7. doi: 10.1097/PAT.0000000000000210.

PubMed [citation]

PMID:: 25551302

The spectrum of phenylketonuria genotypes in the Armenian population: identification of three novel mutant PAH alleles.

Kostandyan N, Britschgi C, Matevosyan A, Oganezova A, Davtyan A, Blau N, Steinmann B, Thöny B.

Mol Genet Metab. 2011;104 Suppl:S93-6. doi: 10.1016/j.ymgme.2011.08.006. Epub 2011 Aug 12.

PubMed [citation]

PMID:: 21890392

See all PubMed Citations (5)

Details of each submission

From Inserm U 954, Faculté de Médecine de Nancy, SCV000243911.1

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

Description

Converted during submission to Likely pathogenic.

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV003934427.1

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

Description

Variant summary: PAH c.836C>T (p.Pro279Leu) results in a non-conservative amino acid change to a highly conserved residue (HGMD) located in the Aromatic amino acid hydroxylase, C-terminal (IPR019774) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251286 control chromosomes. c.836C>T has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria, Kostandyan_2011, Williams_2015, Hillert_2020), and some were reported as compound heterozygous with other pathogenic variants. These data indicate that the variant is very likely to be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. 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 Baylor Genetics, SCV004209633.1

#	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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004294281.1

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

Description

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 279 of the PAH protein (p.Pro279Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 21890392, 32668217). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 208181). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PAH protein function with a positive predictive value of 80%. This variant disrupts the p.Pro279 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004848714.1

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

Description

The p.Pro279Leu variant in PAH has been reported in 4 individuals with phenylketonuria all of whom were compound heterozygous with a second pathogenic variant (Kostandyan 2011 PMID: 21890392, Hillert 2020 PMID: 32668217), and segregated with disease in one affected sibling (Kostandyan 2011 PMID: 21890392). The variant was absent in large population studies. Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive phenylketonuria. ACMG/AMP criteria applied: PM3_VeryStrong, PM2_Supporting, PP1, PP3.

#	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

Last Updated: Sep 29, 2024

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