NM_000277.3(PAH):c.281T>G (p.Ile94Ser) AND Phenylketonuria

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Oct 7, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000673537.2

Allele description [Variation Report for NM_000277.3(PAH):c.281T>G (p.Ile94Ser)]

NM_000277.3(PAH):c.281T>G (p.Ile94Ser)

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.281T>G (p.Ile94Ser)

HGVS:

NC_000012.12:g.102894806A>C
NG_008690.2:g.68605T>G
NM_000277.3:c.281T>GMANE SELECT
NM_001354304.2:c.281T>G
NP_000268.1:p.Ile94Ser
NP_001341233.1:p.Ile94Ser
NC_000012.11:g.103288584A>C
NM_000277.1:c.281T>G

Protein change:

I94S

Links:

dbSNP: rs62508677

NCBI 1000 Genomes Browser:

rs62508677

Molecular consequence:

NM_000277.3:c.281T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354304.2:c.281T>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

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CD36_25570 [Candida dubliniensis CD36]
CD36_25570 [Candida dubliniensis CD36]
Gene ID:8050062

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000798749	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Uncertain significance (Mar 23, 2018)	unknown	clinical testing	PubMed (8) [See all records that cite these PMIDs] 16198137, 24939588, 10679941, 10980574, 19292873, 9634518, 17924342, 10394930 Citation Link,
SCV004296185	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 7, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 16198137, 32668217, 28492532 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000798749

Counsyl

criteria provided, single submitter

(Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))

Uncertain significance
(Mar 23, 2018)

unknown

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

Citation Link,

SCV004296185

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 7, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

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

Citations

PubMed

Linking genotypes database with locus-specific database and genotype-phenotype correlation in phenylketonuria.

Wettstein S, Underhaug J, Perez B, Marsden BD, Yue WW, Martinez A, Blau N.

Eur J Hum Genet. 2015 Mar;23(3):302-9. doi: 10.1038/ejhg.2014.114. Epub 2014 Jun 18.

PubMed [citation]

PMID:: 24939588
PMCID:: PMC4326710

Phenylketonuria and hyperphenylalaninemia in eastern Germany: a characteristic molecular profile and 15 novel mutations.

Hennermann JB, Vetter B, Wolf C, Windt E, Bührdel P, Seidel J, Mönch E, Kulozik AE.

Hum Mutat. 2000;15(3):254-60.

PubMed [citation]

PMID:: 10679941

See all PubMed Citations (10)

Details of each submission

From Counsyl, SCV000798749.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

#	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, SCV004296185.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces isoleucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 94 of the PAH protein (p.Ile94Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hyperphenylalaninemia (PKU) (PMID: 16198137, 32668217; BIOPKU http://www.biopku.org). ClinVar contains an entry for this variant (Variation ID: 102644). 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. This variant disrupts the p.Ile94 amino acid residue in PAH. Other variant(s) that disrupt this residue have been observed in individuals with PAH-related conditions (PMID: 32668217; BIOPKU http://www.biopku.org), which suggests that this may be a clinically significant amino acid residue. 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

Last Updated: Feb 20, 2024

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