NM_000277.3(PAH):c.1101G>A (p.Leu367=) AND Phenylketonuria

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jul 23, 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:: RCV000758108.10

Allele description [Variation Report for NM_000277.3(PAH):c.1101G>A (p.Leu367=)]

NM_000277.3(PAH):c.1101G>A (p.Leu367=)

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.1101G>A (p.Leu367=)

Other names:

NM_000277.2(PAH):c.1101G>A

HGVS:

NC_000012.12:g.102843744C>T
NG_008690.2:g.119667G>A
NM_000277.3:c.1101G>AMANE SELECT
NM_001354304.2:c.1101G>A
NP_000268.1:p.Leu367=
NP_001341233.1:p.Leu367=
NC_000012.11:g.103237522C>T
NM_000277.1:c.1101G>A

Links:

dbSNP: rs62508648

NCBI 1000 Genomes Browser:

rs62508648

Molecular consequence:

NM_000277.3:c.1101G>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001354304.2:c.1101G>A - synonymous variant - [Sequence Ontology: SO:0001819]

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
SCV000886582	ClinGen PAH Variant Curation Expert Panel	reviewed by expert panel (ClinGen PAH ACMG Specifications v1)	Uncertain significance (Jul 23, 2023)	germline	curation	Citation Link,
SCV001601592	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 27, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 16256386, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000886582

ClinGen PAH Variant Curation Expert Panel

reviewed by expert panel

(ClinGen PAH ACMG Specifications v1)

Uncertain significance
(Jul 23, 2023)

germline

curation

Citation Link,

SCV001601592

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 27, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

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

Citations

PubMed

Phenylketonuria mutations in Northern China.

Song F, Qu YJ, Zhang T, Jin YW, Wang H, Zheng XY.

Mol Genet Metab. 2005 Dec;86 Suppl 1:S107-18. Epub 2005 Oct 26.

PubMed [citation]

PMID:: 16256386

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

Details of each submission

From ClinGen PAH Variant Curation Expert Panel, SCV000886582.3

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

Description

The c.1101G>A (p.Leu367=) variant in PAH is reported in an individual with Classic PKU, in trans with p.R243Q. (PMID: 16256386) This variant is absent in population databases. Two splicing algorthms predict a deleterious effect (Human splicing finder: potential alteration of splicing; MaxEnt scan: +571.94% Variation). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2_supporting, PM3, PP4, 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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001601592.4

#	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 affects codon 367 of the PAH mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PAH protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with phenylketonuria (PMID: 16256386). ClinVar contains an entry for this variant (Variation ID: 102526). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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: Sep 29, 2024

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