NM_000277.3(PAH):c.434A>T (p.Asp145Val) AND Phenylketonuria

Germline classification:: Likely pathogenic (7 submissions)
Last evaluated:: Dec 10, 2018
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:: RCV000546355.21

Allele description [Variation Report for NM_000277.3(PAH):c.434A>T (p.Asp145Val)]

NM_000277.3(PAH):c.434A>T (p.Asp145Val)

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.434A>T (p.Asp145Val)

Other names:

NM_000277.2(PAH):c.434A>T

HGVS:

NC_000012.12:g.102877469T>A
NG_008690.2:g.85942A>T
NM_000277.3:c.434A>TMANE SELECT
NM_001354304.2:c.434A>T
NP_000268.1:p.Asp145Val
NP_001341233.1:p.Asp145Val
NC_000012.11:g.103271247T>A
NM_000277.1:c.434A>T
P00439:p.Asp145Val

Protein change:

D145V

Links:

UniProtKB: P00439#VAR_011566; dbSNP: rs140175796

NCBI 1000 Genomes Browser:

rs140175796

Molecular consequence:

NM_000277.3:c.434A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354304.2:c.434A>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
SCV000629192	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 30, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 8659548, 26666653, 27121329, 28492532
SCV000696447	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Oct 27, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 25087612, 24368688, 8659548, 26666653, 17096675, 27121329, 10541324 Citation Link,
SCV000886564	ClinGen PAH Variant Curation Expert Panel	reviewed by expert panel (ClinGen PAH ACMG Specifications v1)	Likely pathogenic (Dec 10, 2018)	germline	curation	PubMed (7) [See all records that cite these PMIDs] 24368688, 8659548, 11385716, 26666653, 23514811, 17096675, 12655553 Citation Link,
SCV000914556	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Pathogenic (Dec 11, 2018)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 8659548, 19786003, 24368688, 26666653, 12655553, 10598814, 11385716 Citation Link,
SCV001132449	Counsyl	no assertion criteria provided	Likely pathogenic (Apr 14, 2017)	unknown	clinical testing	PubMed (15) [See all records that cite these PMIDs] 12655553, 11385716, 17924342, 10598814, 10541324, 27121329, 10527663, 8659548, 11678552, 17096675, 11180595, 24368688, 26666653, 19786003, 10394930
SCV001455109	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV004201351	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 27, 2024)	unknown	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	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Pathogenic variants for Mendelian and complex traits in exomes of 6,517 European and African Americans: implications for the return of incidental results.

Tabor HK, Auer PL, Jamal SM, Chong JX, Yu JH, Gordon AS, Graubert TA, O'Donnell CJ, Rich SS, Nickerson DA; NHLBI Exome Sequencing Project., Bamshad MJ.

Am J Hum Genet. 2014 Aug 7;95(2):183-93. doi: 10.1016/j.ajhg.2014.07.006. Epub 2014 Jul 31.

PubMed [citation]

PMID:: 25087612
PMCID:: PMC4129409

See all PubMed Citations (19)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000629192.7

#	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 aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 145 of the PAH protein (p.Asp145Val). This variant is present in population databases (rs140175796, gnomAD 0.01%). This missense change has been observed in individual(s) with phenylalanine levels >180 umol/L findings that are highly specific for hyperphenylalaninemia (PMID: 8659548, 26666653). ClinVar contains an entry for this variant (Variation ID: 102667). 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%. Experimental studies have shown that this missense change affects PAH function (PMID: 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, SCV000696447.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

Variant summary: PAH c.434A>T (p.Asp145Val) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 251484 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (6.4e-05 vs 0.0079), allowing no conclusion about variant significance. c.434A>T has been reported in the literature in several affected individuals with biochemically confirmed mild form of HPA or PKU, and was predicted to be BH4-responsive allele. The following publications have been ascertained in the context of this evaluation (PMID: 25087612, 24368688, 8659548, 26666653, 17096675, 27121329, 10541324). Eight 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 ClinGen PAH Variant Curation Expert Panel, SCV000886564.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (7)

Description

The c.434A>T (p.Asp145Val) PAH variant has been identified in patients with PAH deficiency from the US, Germany, Italy and Spain. BH4 deficiency was excluded. (PMID: 8659548; 11385716; 12655553; 17096675; 23514811) It was detected with known pathogenic variants: V388M (PMID: 8659548), I65T (PMID: 24368688), and R408W (PMID: 26666653). It is found at extremely low frequency (MAF 0.00012 in gnomAD). A deleterious effect is predicted in SIFT, Polyphen2, MutationTaster, and REVEL=0.987. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PP4_Moderate, 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 Illumina Laboratory Services, Illumina, SCV000914556.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

The PAH c.434A>T (p.Asp145Val) missense variant has been reported in seven studies in which it is found in a total of seven individuals in a compound heterozygous state, and in one in a heterozygous state with no second variant detected (Guldberg et al. 1996, Mallolas et al. 1999, Yang et al. 2001, Aulehla-Scholz et al. 2003, Dahri et al. 2010, Ho et al. 2013, Jeannesson-Thivisol et al. 2015). Individuals with the p.Asp145Val variant were described as having mild hyperphenylalaninemia. The p.Asp145Val variant was absent from 620 healthy controls (Aulehla-Scholz et al. 2003, Ho et al. 2014) and is reported at a frequency of 0.00006 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence, the p.Asp145Val variant is classified as pathogenic for phenylalanine hydroxylase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	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 Counsyl, SCV001132449.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (15)

#	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 Natera, Inc., SCV001455109.1

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

#	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, SCV004201351.2

#	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

Last Updated: Oct 13, 2024

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