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NM_000277.3(PAH):c.194T>C (p.Ile65Thr) AND Inborn genetic diseases

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jan 26, 2021
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV004018528.1

Allele description [Variation Report for NM_000277.3(PAH):c.194T>C (p.Ile65Thr)]

NM_000277.3(PAH):c.194T>C (p.Ile65Thr)

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.194T>C (p.Ile65Thr)
Other names:
p.I65T:ATT>ACT; NM_000277.2(PAH):c.194T>C
HGVS:
  • NC_000012.12:g.102894893A>G
  • NG_008690.2:g.68518T>C
  • NM_000277.3:c.194T>CMANE SELECT
  • NM_001354304.2:c.194T>C
  • NP_000268.1:p.Ile65Thr
  • NP_000268.1:p.Ile65Thr
  • NP_001341233.1:p.Ile65Thr
  • NC_000012.11:g.103288671A>G
  • NM_000277.1:c.194T>C
  • NM_000277.2:c.194T>C
  • P00439:p.Ile65Thr
  • c.194T>C (p.Ile65Thr)
Protein change:
I65T; ILE65THR
Links:
UniProtKB: P00439#VAR_000883; OMIM: 612349.0063; dbSNP: rs75193786
NCBI 1000 Genomes Browser:
rs75193786
Molecular consequence:
  • NM_000277.3:c.194T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354304.2:c.194T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Inborn genetic diseases
Identifiers:
MeSH: D030342; MedGen: C0950123

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004998568Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Pathogenic
(Jan 26, 2021) 		germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

In vitro and in vivo correlations for I65T and M1V mutations at the phenylalanine hydroxylase locus.

John SW, Scriver CR, Laframboise R, Rozen R.

Hum Mutat. 1992;1(2):147-53.

PubMed [citation]
PMID:
1301201

The correlation of genotype and phenotype in Portuguese hyperphenylalaninemic patients.

Rivera I, Cabral A, Almeida M, Leandro P, Carmona C, Eusébio F, Tasso T, Vilarinho L, Martins E, Lechner MC, de Almeida IT, Konecki DS, Lichter-Konecki U.

Mol Genet Metab. 2000 Mar;69(3):195-203.

PubMed [citation]
PMID:
10767174
See all PubMed Citations (6)

Details of each submission

From Ambry Genetics, SCV004998568.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

The c.194T>C (p.I65T) alteration is located in coding exon 3 of the PAH gene. This alteration results from a T to C substitution at nucleotide position 194, causing the isoleucine (I) at amino acid position 65 to be replaced by a threonine (T). Based on data from the Genome Aggregation Database (gnomAD), the PAH c.194T>C alteration was observed in 0.03% (83/282610) of total alleles studied, with a frequency of 0.06% (72/129008) in the European (non-Finnish) subpopulation. No homozygotes were observed. The c.194T>C (p.I65T) alteration has been described homozygous and compound heterozygous with a second allele in multiple unrelated families with phenotypes ranging from hyperphenylalaninemia to classic PKU (Couce, 2013; Desviat, 2004; John, 1992; Muntau, 2002; Rivera, 2000). The p.I65 amino acid is conserved in available vertebrate species. In vitro functional studies determined protein expressing the c.194T>C (p.I65T) alteration decreased PAH activity to less than 50% of wild type activity. When observed with a second deleterious alteration, residual PAH activity ranged between 5.5% to 48% (John, 1992; Shen, 2016). The p.I65T alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jan 19, 2025