NM_000277.3(PAH):c.764T>C (p.Leu255Ser) AND Phenylketonuria

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Oct 7, 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:: RCV000000631.81

Allele description [Variation Report for NM_000277.3(PAH):c.764T>C (p.Leu255Ser)]

NM_000277.3(PAH):c.764T>C (p.Leu255Ser)

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.764T>C (p.Leu255Ser)

HGVS:

NC_000012.12:g.102852893A>G
NG_008690.2:g.110518T>C
NM_000277.3:c.764T>CMANE SELECT
NM_001354304.2:c.764T>C
NP_000268.1:p.Leu255Ser
NP_001341233.1:p.Leu255Ser
NC_000012.11:g.103246671A>G
NM_000277.1:c.764T>C
P00439:p.Leu255Ser

Protein change:

L255S; LEU255SER

Links:

UniProtKB: P00439#VAR_000960; OMIM: 612349.0026; dbSNP: rs62642930

NCBI 1000 Genomes Browser:

rs62642930

Molecular consequence:

NM_000277.3:c.764T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354304.2:c.764T>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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000020781	OMIM	no assertion criteria provided	Pathogenic (Apr 1, 1991)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000795922	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (Nov 30, 2017)	unknown	clinical testing	PubMed (5) [See all records that cite these PMIDs] 21953985, 26322415, 9799096, 16256386, 23932990 Citation Link,
SCV001395954	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 7, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 2014802, 29317692, 21953985, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000020781

OMIM

no assertion criteria provided

Pathogenic
(Apr 1, 1991)

germline

literature only

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

SCV000795922

Counsyl

criteria provided, single submitter

(Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))

Likely pathogenic
(Nov 30, 2017)

unknown

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link,

SCV001395954

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 7, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Correlation between genotype and the tetrahydrobiopterin-responsive phenotype in Chinese patients with phenylketonuria.

Tao J, Li N, Jia H, Liu Z, Li X, Song J, Deng Y, Jin X, Zhu J.

Pediatr Res. 2015 Dec;78(6):691-9. doi: 10.1038/pr.2015.167. Epub 2015 Aug 31.

PubMed [citation]

PMID:: 26322415
PMCID:: PMC4700046

Partial characterization and three-dimensional-structural localization of eight mutations in exon 7 of the human phenylalanine hydroxylase gene associated with phenylketonuria.

Bjørgo E, Knappskog PM, Martinez A, Stevens RC, Flatmark T.

Eur J Biochem. 1998 Oct 1;257(1):1-10.

PubMed [citation]

PMID:: 9799096

See all PubMed Citations (8)

Details of each submission

From OMIM, SCV000020781.66

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

Description

In a study of phenylketonuria (PKU; 261600) in U.S. blacks living in Maryland, Hofman et al. (1991) found that 40% of mutant PAH alleles had 1 of 2 previously undescribed haplotypes. Both of these could be derived from known haplotypes by a single event. One of these haplotypes was characterized by a new MspI restriction site, located in intron 8, which was present in 5 of 16 black mutant alleles but was not found in 60 U.S. black controls, 20 U.S. Caucasian controls, or 20 Caucasian mutant PAH alleles. Sequence analysis of DNA from a single individual, homozygous for the MspI-associated haplotype, showed homozygosity for a C-to-T transition at nucleotide 896 in exon 7, resulting in the conversion of leucine-255 to serine (L255S).

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

From Counsyl, SCV000795922.1

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

#	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, SCV001395954.4

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

Description

This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 255 of the PAH protein (p.Leu255Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 2014802, 29317692). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 600). 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. Experimental studies have shown that this missense change affects PAH function (PMID: 21953985). 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

Last Updated: Sep 29, 2024

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