NM_000277.3(PAH):c.964G>A (p.Ala322Thr) AND Phenylketonuria

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Dec 30, 2023
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:: RCV000797233.14

Allele description [Variation Report for NM_000277.3(PAH):c.964G>A (p.Ala322Thr)]

NM_000277.3(PAH):c.964G>A (p.Ala322Thr)

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.964G>A (p.Ala322Thr)

Other names:

NM_000277.1(PAH):c.964G>A

HGVS:

NC_000012.12:g.102846900C>T
NG_008690.2:g.116511G>A
NM_000277.3:c.964G>AMANE SELECT
NM_001354304.2:c.964G>A
NP_000268.1:p.Ala322Thr
NP_001341233.1:p.Ala322Thr
NC_000012.11:g.103240678C>T
NM_000277.1:c.964G>A
P00439:p.Ala322Thr

Protein change:

A322T

Links:

UniProtKB: P00439#VAR_000999; dbSNP: rs62514957

NCBI 1000 Genomes Browser:

rs62514957

Molecular consequence:

NM_000277.3:c.964G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354304.2:c.964G>A - 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
SCV000936782	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 26, 2024)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 23764561, 26322415, 26600521, 27121329, 1301200, 9450897, 21871829, 27469133, 28492532
SCV002790355	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Dec 8, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003826595	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 7, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004209622	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 25, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004222616	ClinGen PAH Variant Curation Expert Panel	reviewed by expert panel (ClinGen PAH ACMG Specifications v1)	Pathogenic (Dec 30, 2023)	germline	curation	PubMed (2) [See all records that cite these PMIDs] 26322415, 18590700 Citation Link

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

Phenylalanine hydroxylase deficiency in the Slovak population: genotype-phenotype correlations and genotype-based predictions of BH4-responsiveness.

Polak E, Ficek A, Radvanszky J, Soltysova A, Urge O, Cmelova E, Kantarska D, Kadasi L.

Gene. 2013 Sep 10;526(2):347-55. doi: 10.1016/j.gene.2013.05.057. Epub 2013 Jun 10.

PubMed [citation]

PMID:: 23764561

Prenatal diagnosis of Chinese families with phenylketonuria.

Liu N, Kong XD, Zhao DH, Wu QH, Li XL, Guo HF, Cui LX, Jiang M, Shi HR.

Genet Mol Res. 2015 Nov 19;14(4):14615-28. doi: 10.4238/2015.November.18.25.

PubMed [citation]

PMID:: 26600521

See all PubMed Citations (11)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000936782.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 322 of the PAH protein (p.Ala322Thr). This variant is present in population databases (rs62514957, gnomAD 0.03%). This missense change has been observed in individual(s) with PAH-related conditions (PMID: 23764561, 26322415, 26600521, 27121329). 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: 102912). 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%. This variant disrupts the p.Ala322 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1301200, 9450897, 21871829, 27469133). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 Fulgent Genetics, Fulgent Genetics, SCV002790355.1

#	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 Revvity Omics, Revvity, SCV003826595.2

#	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	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004209622.2

#	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 ClinGen PAH Variant Curation Expert Panel, SCV004222616.1

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

Description

The NM_000277.1(PAH):c.964G>A (p.Ala322Thr) variant is a missense variant in exon 9/13 of PAH. The variant has been found to reduce PAH enzymatic activity to 11% of wild-type in an Intinc system and 20% of wild-type in a cDNA system in transfected cells (PMID: 18590700) (PS3_supporting). The variant has been previously noted in at least four PKU patients among whom BH4 deficiency was excluded, including in trans with Pathogenic or Likely Pathogenic alleles (PM3_VeryStrong (4 points); PP4_Moderate). The variant has been previously reported in a Chinese patient with mild hyperphenylalanemia in trans with the p.R111* variant (Pathogenic in ClinVar and by the ClinGen PAH VCEP); BH4 deficiency was excluded via analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes (PMID: 30050108; PMID: 26322415). It has been noted in a Spanish patient with mild hyperphenylalanemia in trans with the p.S349P variant (Pathogenic in ClinVar and by the ClinGen PAH VCEP); BH4 deficiency was excluded analyzing urinary pterin levels as well as by measuring the dihydropteridine reductase activity (PMID: 27121329). It was found in a Slovak patient with mild hyperphenylalanemia in trans with the p.A403V variant (Pathogenic in ClinVar and by the ClinGen PAH VCEP); BH4 deficiency was excluded (PMID: 23764561). It has been noted in a Chinese patient with PKU (plasma Phe >120 umol/L; no further specification) and BH4 deficiency excluded in trans with p.R176* (Pathogenic in ClinVar and by the ClinGen PAH VCEP) (PMID: 26600521). Another missense variant at the same site, p.A322G, is classified Pathogenic in ClinVar (ID 616) and by the ClinGen PAH VCEP. 18 heterozygotes and zero homozygotes are present for the variant in gnomAD, corresponding to a global frequency of 0.0000716 and a maximum population frequency of 0.000261; these frequencies exceed the 0.0002 cutoff for use of PM2, but is lower than the 0.002 cutoff for use of BS1. The variant is predicted damaging by multiple in-silico missense predictors, including REVEL (REVEL score 0.889) (PP3). Classification: Pathogenic Supporting Criteria: PS3_supporting; PM3_VeryStrong; 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

Last Updated: Sep 29, 2024

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