NM_000277.3(PAH):c.280A>G (p.Ile94Val) AND Phenylketonuria

Germline classification:: Uncertain significance (4 submissions)
Last evaluated:: Oct 15, 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:: RCV001114785.7

Allele description [Variation Report for NM_000277.3(PAH):c.280A>G (p.Ile94Val)]

NM_000277.3(PAH):c.280A>G (p.Ile94Val)

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.280A>G (p.Ile94Val)

HGVS:

NC_000012.12:g.102894807T>C
NG_008690.2:g.68604A>G
NM_000277.3:c.280A>GMANE SELECT
NM_001354304.2:c.280A>G
NP_000268.1:p.Ile94Val
NP_001341233.1:p.Ile94Val
NC_000012.11:g.103288585T>C
NC_000012.11:g.103288585T>C
NM_000277.1:c.280A>G

Protein change:

I94V

Links:

dbSNP: rs528078207

NCBI 1000 Genomes Browser:

rs528078207

Molecular consequence:

NM_000277.3:c.280A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354304.2:c.280A>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

Recent activity

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ribosomal protein S12, partial (chloroplast) [Aquilegia alpina]
ribosomal protein S12, partial (chloroplast) [Aquilegia alpina]
gi|453059222|gb|AGG21540.1|

Protein
Androsace maxima voucher Herb. W. Gutermann:W. Gutermann 37180 maturase K (matK)...
Androsace maxima voucher Herb. W. Gutermann:W. Gutermann 37180 maturase K (matK) gene, partial cds; chloroplast
gi|702066207|gb|KF907901.1|

Nucleotide
Androsace barbulata voucher WU:Schneeweiss et al. 8185 maturase K (matK) gene, p...
Androsace barbulata voucher WU:Schneeweiss et al. 8185 maturase K (matK) gene, partial cds; chloroplast
gi|702066195|gb|KF907895.1|

Nucleotide
Androsace spinulifera voucher WU:Y.-P. Guo & G.-Y. Rao 0303 maturase K (matK) ge...
Androsace spinulifera voucher WU:Y.-P. Guo & G.-Y. Rao 0303 maturase K (matK) gene, partial cds; chloroplast
gi|702066193|gb|KF907894.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001272693	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Apr 27, 2017)	germline	clinical testing	Citation Link,
SCV001448613	ClinGen PAH Variant Curation Expert Panel	reviewed by expert panel (ClinGen PAH ACMG Specifications v1)	Uncertain significance (Oct 15, 2020)	germline	curation	PubMed (2) [See all records that cite these PMIDs] 30459323, 28982351 Citation Link,
SCV002775201	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 3, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003270640	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 5, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 28982351, 28492532

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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

Mutational and phenotypic spectrum of phenylalanine hydroxylase deficiency in Zhejiang Province, China.

Chen T, Xu W, Wu D, Han J, Zhu L, Tong F, Yang R, Zhao Z, Jiang P, Shu Q.

Sci Rep. 2018 Nov 20;8(1):17137. doi: 10.1038/s41598-018-35373-9.

PubMed [citation]

PMID:: 30459323
PMCID:: PMC6244417

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

See all PubMed Citations (4)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV001272693.1

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

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

#	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, SCV001448613.1

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

Description

This c.280A>G (p.Ile94Val) variant in PAH was reported in at least three patients with PAH deficiency. BH4 deficiency was ruled out through a BH4 loading test, a urinary pterin analysis, and a DHPR activity assay in at least one case (PMID: 30747360, 30459323, and 28982351). This variant is present in the East Asian at a frequency of 0.00160, higher than the PAH Variant Curation Expert Panel cutoff of 0.0002. Computational evidence is conflicting in the predicted effect of this variant. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4_moderate.

#	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, SCV002775201.1

#	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 Invitae, SCV003270640.1

#	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 isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 94 of the PAH protein (p.Ile94Val). This variant is present in population databases (rs528078207, gnomAD 0.2%). This missense change has been observed in individual(s) with clinical features of hyperphenylalaninemia (PMID: 28982351). ClinVar contains an entry for this variant (Variation ID: 883981). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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: Dec 24, 2023

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