NM_000277.3(PAH):c.718T>G (p.Phe240Val) AND Phenylketonuria

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Nov 9, 2020
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:: RCV000667600.8

Allele description [Variation Report for NM_000277.3(PAH):c.718T>G (p.Phe240Val)]

NM_000277.3(PAH):c.718T>G (p.Phe240Val)

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.718T>G (p.Phe240Val)

Other names:

NM_000277.2(PAH):c.718T>G; p.Phe240Val

HGVS:

NC_000012.12:g.102852939A>C
NG_008690.2:g.110472T>G
NM_000277.3:c.718T>GMANE SELECT
NM_001354304.2:c.718T>G
NP_000268.1:p.Phe240Val
NP_001341233.1:p.Phe240Val
NC_000012.11:g.103246717A>C
NM_000277.1:c.718T>G

Protein change:

F240V

Links:

dbSNP: rs62507337

NCBI 1000 Genomes Browser:

rs62507337

Molecular consequence:

NM_000277.3:c.718T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354304.2:c.718T>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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SRS7995939 (1)
SRA
eif2d [Seriola dumerili]
eif2d [Seriola dumerili]
Gene ID:111217304

Gene
111217304[uid] AND (alive[prop]) (1)
Gene
Crossocheilus reticulatus
Crossocheilus reticulatus
Crossocheilus reticulatus RefSeq Genome

BioProject
POLR1B [Otolemur garnettii]
POLR1B [Otolemur garnettii]
Gene ID:100945829

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000792078	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Uncertain significance (Jun 8, 2017)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV002301684	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 16, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 32668217, 28492532
SCV002540119	ClinGen PAH Variant Curation Expert Panel	reviewed by expert panel (ClinGen PAH ACMG Specifications v1)	Uncertain significance (Nov 9, 2020)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000792078

Counsyl

criteria provided, single submitter

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

Uncertain significance
(Jun 8, 2017)

unknown

clinical testing

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

Citation Link,

SCV002301684

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 16, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV002540119

ClinGen PAH Variant Curation Expert Panel

reviewed by expert panel

(ClinGen PAH ACMG Specifications v1)

Uncertain significance
(Nov 9, 2020)

germline

curation

Citation Link

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

The Genetic Landscape and Epidemiology of Phenylketonuria.

Hillert A, Anikster Y, Belanger-Quintana A, Burlina A, Burton BK, Carducci C, Chiesa AE, Christodoulou J, Đorđević M, Desviat LR, Eliyahu A, Evers RAF, Fajkusova L, Feillet F, Bonfim-Freitas PE, Giżewska M, Gundorova P, Karall D, Kneller K, Kutsev SI, Leuzzi V, Levy HL, et al.

Am J Hum Genet. 2020 Aug 6;107(2):234-250. doi: 10.1016/j.ajhg.2020.06.006. Epub 2020 Jul 14.

PubMed [citation]

PMID:: 32668217
PMCID:: PMC7413859

See all PubMed Citations (3)

Details of each submission

From Counsyl, SCV000792078.1

#	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, SCV002301684.3

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

Description

This sequence change replaces phenylalanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 240 of the PAH protein (p.Phe240Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hyperphenylalaninemia (Invitae). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Phe240 amino acid residue in PAH. Other variant(s) that disrupt this residue have been observed in individuals with PAH-related conditions (PMID: 32668217), which suggests that this may be a clinically significant amino acid residue. 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. ClinVar contains an entry for this variant (Variation ID: 102801).

#	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 ClinGen PAH Variant Curation Expert Panel, SCV002540119.1

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

Description

The c.718T>G (p.Phe240Val) variant in PAH has not been reported in the literature detected in an affected patient to our knowledge. This variant is absent from ExAC, gnomAD, 1000G, and ESP. A deleterious effect is predicted in SIFT, Polyphen-2, MutationTaster, and REVEL=0.978. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, 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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