NM_000277.3(PAH):c.140C>T (p.Ala47Val) AND Phenylketonuria

Germline classification:: Likely pathogenic (4 submissions)
Last evaluated:: May 22, 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:: RCV001200011.7

Allele description [Variation Report for NM_000277.3(PAH):c.140C>T (p.Ala47Val)]

NM_000277.3(PAH):c.140C>T (p.Ala47Val)

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.140C>T (p.Ala47Val)

HGVS:

NC_000012.12:g.102912819G>A
NG_008690.2:g.50592C>T
NM_000277.3:c.140C>TMANE SELECT
NM_001354304.2:c.140C>T
NP_000268.1:p.Ala47Val
NP_001341233.1:p.Ala47Val
NC_000012.11:g.103306597G>A
NM_000277.1:c.140C>T
NM_000277.2(PAH):c.140C>T
P00439:p.Ala47Val

Protein change:

A47V; ALA47VAL

Links:

UniProtKB: P00439#VAR_000876; OMIM: 612349.0056; dbSNP: rs118203925

NCBI 1000 Genomes Browser:

rs118203925

Molecular consequence:

NM_000277.3:c.140C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354304.2:c.140C>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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001370868	ClinGen PAH Variant Curation Expert Panel	reviewed by expert panel (ClinGen PAH ACMG Specifications v1)	Likely pathogenic (May 22, 2020)	germline	curation	PubMed (4) [See all records that cite these PMIDs] 24368688, 27121329, 23514811, 9634518 Citation Link,
SCV001590614	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 22, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 24368688, 11161839, 11326337, 17924342, 27121329, 28492532
SCV004038881	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Aug 10, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 24368688, 11161839, 26542770, 30037505, 27121329, 11326337 Citation Link,
SCV005053811	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 18, 2024)	unknown	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, curation
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Molecular epidemiology and genotype-phenotype correlation in phenylketonuria patients from South Spain.

Bueno MA, González-Lamuño D, Delgado-Pecellín C, Aldámiz-Echevarría L, Pérez B, Desviat LR, Couce ML.

J Hum Genet. 2013 May;58(5):279-84. doi: 10.1038/jhg.2013.16. Epub 2013 Mar 21.

PubMed [citation]

PMID:: 23514811

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 (11)

Details of each submission

From ClinGen PAH Variant Curation Expert Panel, SCV001370868.1

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

Description

The c.140C>T (p.Ala47Val) variant in PAH has been reported in 3 individuals with MHP (BH4 deficiency excluded). (PMID: 24368688, 27121329). This variant has extremely low frequency in gnomAD MAF=0.00001. This variant was detected with pathogenic variants p.E280K (parental analysis not reported), p.Glu178Gly, c.1066-11G>A (segregation analysis done). Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong.

#	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, SCV001590614.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 47 of the PAH protein (p.Ala47Val). This variant is present in population databases (rs118203925, gnomAD 0.0009%). This missense change has been observed in individual(s) with PAH-related conditions (PMID: 24368688, 27121329). ClinVar contains an entry for this variant (Variation ID: 630). 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 not expected to disrupt PAH protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PAH function (PMID: 11161839, 11326337, 17924342, 27121329). 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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004038881.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

Variant summary: PAH c.140C>T (p.Ala47Val) results in a non-conservative amino acid change located in the ACT domain (IPR002912) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251412 control chromosomes (gnomAD). c.140C>T has been reported in the literature in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) and -mild hyperphenylalaninemia (examples: Aldamiz-Echevarria_2016, Bayat_2016, Ho_2013). These data indicate that the variant is likely to be associated with disease. Experimental studies have shown that this missense change affects PAH function (examples: Gjetting_MGM_2001, Gjetting_AJHG_2001, and Himmelreich_2018). The following publications have been ascertained in the context of this evaluation (PMID: 11161839, 11326337, 30037505, 27121329, 24368688, and 26542770). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. 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, SCV005053811.1

#	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

Last Updated: Sep 29, 2024

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