NM_000277.3(PAH):c.293T>C (p.Leu98Ser) AND Phenylketonuria

Germline classification:: Likely pathogenic (5 submissions)
Last evaluated:: Jan 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:: RCV000675074.15

Allele description [Variation Report for NM_000277.3(PAH):c.293T>C (p.Leu98Ser)]

NM_000277.3(PAH):c.293T>C (p.Leu98Ser)

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.293T>C (p.Leu98Ser)

Other names:

NM_000277.2(PAH):c.293T>C

HGVS:

NC_000012.12:g.102894794A>G
NG_008690.2:g.68617T>C
NM_000277.3:c.293T>CMANE SELECT
NM_001354304.2:c.293T>C
NP_000268.1:p.Leu98Ser
NP_001341233.1:p.Leu98Ser
NC_000012.11:g.103288572A>G
NM_000277.1:c.293T>C
P00439:p.Leu98Ser

Protein change:

L98S; LEU98SER

Links:

UniProtKB: P00439#VAR_000891; OMIM: 612349.0053; dbSNP: rs62517167

NCBI 1000 Genomes Browser:

rs62517167

Molecular consequence:

NM_000277.3:c.293T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354304.2:c.293T>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

Clear Turn Off Turn On

tubulin-folding cofactor B [Arachis duranensis]
tubulin-folding cofactor B [Arachis duranensis]
gi|1011992306|ref|XP_015940627.1|

Protein
putative P2Y purinoceptor 10 isoform X4 [Pan troglodytes]
putative P2Y purinoceptor 10 isoform X4 [Pan troglodytes]
gi|1034193129|ref|XP_016799571.1|

Protein
homoserine kinase [Aspergillus fumigatus Af293]
homoserine kinase [Aspergillus fumigatus Af293]
gi|146324059|ref|XP_754050.2|

Protein
alpha-glucosidase MAL32 [Saccharomyces cerevisiae S288C]
alpha-glucosidase MAL32 [Saccharomyces cerevisiae S288C]
gi|398365967|ref|NP_009858.3|

Protein
Trichophyton benhamiae CBS 112371 cytochrome P450 alkane hydroxylase, putative (...
Trichophyton benhamiae CBS 112371 cytochrome P450 alkane hydroxylase, putative (ARB_01737), partial mRNA
gi|302499974|ref|XM_003011936.1|

Nucleotide

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000800569	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Uncertain significance (Jul 27, 2017)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 8364546, 10527663 Citation Link,
SCV000886557	ClinGen PAH Variant Curation Expert Panel	reviewed by expert panel (ClinGen PAH ACMG Specifications v1)	Likely pathogenic (Jan 14, 2022)	germline	curation	PubMed (2) [See all records that cite these PMIDs] 9634518, 8364546 Citation Link,
SCV001583733	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 30, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 26322415, 26542770, 28492532
SCV004209695	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 11, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004847267	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Feb 6, 2023)	germline	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

The structural basis of phenylketonuria.

Erlandsen H, Stevens RC.

Mol Genet Metab. 1999 Oct;68(2):103-25. Review.

PubMed [citation]

PMID:: 10527663

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 (7)

Details of each submission

From Counsyl, SCV000800569.1

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

#	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, SCV000886557.3

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

Description

The c.293T>C (p.Leu98Ser) variant in PAH has been reported as homozygous in a Pakistani patient with mild PKU (BH4 deficiency excluded) (PMID: 8364546, 9634518, 26542770) This variant has an extremely low frequency in gnomAD v2.1.1 (MAF=0.0001307). A deleterious effect is predicted in SIFT, Polyphen-2, MutationTaster, and REVEL=0.846. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_supporting, 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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001583733.3

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

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Leu98 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26322415). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. This variant has been observed in individual(s) with hyperphenylalaninemia (PMID: 26542770). ClinVar contains an entry for this variant (Variation ID: 627). This sequence change replaces leucine with serine at codon 98 of the PAH protein (p.Leu98Ser). The leucine residue is highly conserved and there is a large physicochemical difference between leucine and serine. This variant is present in population databases (rs62517167, ExAC 0.006%).

#	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, SCV004209695.2

#	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

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004847267.1

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

Description

The p.Leu98Ser variant in PAH has been reported in at least 4 individuals with phenylalanine hydroxylase deficiency (mild non-PKU hyperphenylalaninemia, mild PKU) who were either homozygous or compound heterozygous with another pathogenic variant (Guldberg 1993 PMID: 8364546, Bayat 2016 PMID: 26542770, Hillert 2020 PMID: 32668217). It has also been identified in 0.02% (1/4822) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has been reported as likely pathogenic by the ClinGen PAH Variant Curation Expert Panel using the ACMG-AMP criteria specific for phenylalanine hydroxylase variants (Zastrow 2018 PMID: 30311390) and is curated in the FDA-recognized human genetic variant ClinVar database (Variation ID 627). Computational prediction tools and conservation analyses suggest the variant may impact the protein this codon (p.Leu98Val) have been identified in individuals with phenylalanine hydroxylase deficiency and is classified as pathogenic by the ClinGen PAH Variant Curation Expert Panel. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic autosomal recessive phenylalanine hydroxylase deficiency. ACMG/AMP Criteria applied: PM3, PM2_Supporting, PP3, PP4_Moderate, PM5.

#	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: Oct 13, 2024

ClinVar

Relating variation to medicine