NM_000277.3(PAH):c.305T>C (p.Ile102Thr) AND Phenylketonuria

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Aug 31, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001580454.6

Allele description [Variation Report for NM_000277.3(PAH):c.305T>C (p.Ile102Thr)]

NM_000277.3(PAH):c.305T>C (p.Ile102Thr)

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.305T>C (p.Ile102Thr)

HGVS:

NC_000012.12:g.102894782A>G
NG_008690.2:g.68629T>C
NM_000277.3:c.305T>CMANE SELECT
NM_001354304.2:c.305T>C
NP_000268.1:p.Ile102Thr
NP_001341233.1:p.Ile102Thr
NC_000012.11:g.103288560A>G
NM_000277.1:c.305T>C

Protein change:

I102T

Links:

dbSNP: rs62508591

NCBI 1000 Genomes Browser:

rs62508591

Molecular consequence:

NM_000277.3:c.305T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354304.2:c.305T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Phenylketonuria (PKU)
Synonyms:: FOLLING DISEASE; OLIGOPHRENIA PHENYLPYRUVICA; Phenylketonurias
Identifiers:: MONDO: MONDO:0009861; MedGen: C0031485; Orphanet: 716; OMIM: 261600

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001810538	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 22, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003441162	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 31, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 30389586, 32668217, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001810538

Genome-Nilou Lab

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jul 22, 2021)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV003441162

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 31, 2022)

germline

clinical testing

PubMed (3)
[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	no	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

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

A comprehensive study of phenylalanine hydroxylase gene mutations in the Iranian phenylketonuria patients.

Esfahani MS, Vallian S.

Eur J Med Genet. 2019 Sep;62(9):103559. doi: 10.1016/j.ejmg.2018.10.011. Epub 2018 Oct 30.

PubMed [citation]

PMID:: 30389586

See all PubMed Citations (4)

Details of each submission

From Genome-Nilou Lab, SCV001810538.1

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV003441162.3

#	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 threonine, which is neutral and polar, at codon 102 of the PAH protein (p.Ile102Thr). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. 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 expected to disrupt PAH protein function. ClinVar contains an entry for this variant (Variation ID: 102648). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 30389586, 32668217).

#	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 25, 2025

ClinVar

Relating variation to medicine