NM_000277.3(PAH):c.158G>A (p.Arg53His) AND Phenylketonuria

Clinical significance:Uncertain significance (Last evaluated: Aug 10, 2018)
Review status:3 stars out of maximum of 4 stars
reviewed by expert panel

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Based on:: 9 submissions [Details]
Record status:: current
Accession:: RCV000490373.20

Allele description [Variation Report for NM_000277.3(PAH):c.158G>A (p.Arg53His)]

NM_000277.3(PAH):c.158G>A (p.Arg53His)

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.158G>A (p.Arg53His)

Other names:

NM_000277.2(PAH):c.158G>A

HGVS:

NC_000012.12:g.102912801C>T
NG_008690.2:g.50610G>A
NM_000277.3:c.158G>AMANE SELECT
NM_001354304.2:c.158G>A
NP_000268.1:p.Arg53His
NP_001341233.1:p.Arg53His
NC_000012.11:g.103306579C>T
NM_000277.1:c.158G>A
NM_000277.2:c.158G>A
P00439:p.Arg53His

Protein change:

R53H

Links:

UniProtKB: P00439#VAR_000878; dbSNP: rs118092776

NCBI 1000 Genomes Browser:

rs118092776

Molecular consequence:

NM_000277.3:c.158G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354304.2:c.158G>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
SCV000267433	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	criteria provided, single submitter ACMG Guidelines, 2015	Uncertain significance (Mar 18, 2016)	germline	reference population	PubMed (2) [See all records that cite these PMIDs] 9452061, 25741868
SCV000754088	Invitae	criteria provided, single submitter Invitae Variant Classification Sherloc (09022015)	Benign (Nov 4, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000852170	ClinGen PAH Variant Curation Expert Panel	reviewed by expert panel ClinGen PAH ACMG Specifications v1	Uncertain significance (Aug 10, 2018)	germline	curation	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000853180	SingHealth Duke-NUS Institute of Precision Medicine	no assertion criteria provided	Likely benign (Jun 7, 2017)	germline	curation
SCV001138806	Mendelics	criteria provided, single submitter Mendelics Assertion Criteria 2017	Uncertain significance (May 28, 2019)	unknown	clinical testing	Citation Link,
SCV001266460	Illumina Laboratory Services, Illumina	criteria provided, single submitter ICSL Variant Classification Criteria 13 December 2019	Likely benign (Apr 27, 2017)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 19915519, 16253218, 15503242, 16256386, 18294361, 12655553, 9452061 Citation Link,
SCV001455418	Natera, Inc.	no assertion criteria provided	Benign (Jan 6, 2020)	germline	clinical testing
SCV001716364	Genome-Nilou Lab	criteria provided, single submitter ACMG Guidelines, 2015	Uncertain significance (May 18, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003816612	PerkinElmer Genomics	criteria provided, single submitter ACMG Guidelines, 2015	Uncertain significance (Nov 8, 2022)	germline	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	no	not provided	not provided	not provided	not provided	not provided	clinical testing, curation
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
East Asian	germline	unknown	3	not provided	not provided	not provided	not provided	reference population

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):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

The mutation spectrum of the phenylalanine hydroxylase (PAH) gene and associated haplotypes reveal ethnic heterogeneity in the Taiwanese population.

Liang Y, Huang MZ, Cheng CY, Chao HK, Fwu VT, Chiang SH, Hsiao KJ, Niu DM, Su TS.

J Hum Genet. 2014 Mar;59(3):145-52. doi: 10.1038/jhg.2013.136. Epub 2014 Jan 9.

PubMed [citation]

PMID:: 24401910

See all PubMed Citations (10)

Details of each submission

From Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center, SCV000267433.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	East Asian	3	not provided	not provided	reference population	PubMed (2)

#	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		3	not provided	not provided	not provided

From Invitae, SCV000754088.6

#	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 ClinGen PAH Variant Curation Expert Panel, SCV000852170.4

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

Description

PAH-specific ACMG/AMP criteria applied: BS1: MAF=0.01596 in ExAC (138/8648) and 0.0104 in gnomAD (265/18868 with 3 homozygotes); PP4: Detected in a patient with mild hyperphe (PMID:24401910); PM3: Detected with V388L (LP) (PMID:24401910). In summary this variant meets criteria to be classified as uncertain significance for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (BS1, PP4, PM3).

#	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 SingHealth Duke-NUS Institute of Precision Medicine, SCV000853180.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Mendelics, SCV001138806.1

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

From Illumina Laboratory Services, Illumina, SCV001266460.1

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

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

#	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 Natera, Inc., SCV001455418.1

#	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 Genome-Nilou Lab, SCV001716364.1

#	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	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From PerkinElmer Genomics, SCV003816612.1

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

Last Updated: Nov 25, 2023

Relating variation to medicine