NM_000277.3(PAH):c.284_285delinsCA (p.Ile95Thr) AND Phenylketonuria

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Jan 25, 2020
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:: RCV000106353.5

Allele description [Variation Report for NM_000277.3(PAH):c.284_285delinsCA (p.Ile95Thr)]

NM_000277.3(PAH):c.284_285delinsCA (p.Ile95Thr)

Gene:

PAH:phenylalanine hydroxylase [Gene - OMIM - HGNC]

Variant type:

Indel

Cytogenetic location:

12q23.2

Genomic location:

Preferred name:

NM_000277.3(PAH):c.284_285delinsCA (p.Ile95Thr)

HGVS:

NC_000012.12:g.102894802_102894803delinsTG
NG_008690.2:g.68608_68609delinsCA
NM_000277.3:c.284_285delinsCAMANE SELECT
NM_001354304.2:c.284_285delinsCA
NP_000268.1:p.Ile95Thr
NP_001341233.1:p.Ile95Thr
NC_000012.11:g.103288580_103288581delinsTG
NC_000012.12:g.102894802_102894803delGAinsTG
NM_000277.1:c.284_285delTCinsCA
NM_000277.1:c.284_285delinsCA
NM_000277.2(PAH):c.284_285delTCinsCA
p.Ile95Thr

Protein change:

I95T

Links:

dbSNP: rs281865432

NCBI 1000 Genomes Browser:

rs281865432

Molecular consequence:

NM_000277.3:c.284_285delinsCA - missense variant - [Sequence Ontology: SO:0001583]
NM_001354304.2:c.284_285delinsCA - 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
SCV000143852	Inserm U 954, Faculté de Médecine de Nancy	no assertion criteria provided	probable-pathogenic	unknown	not provided
SCV001250558	ClinGen PAH Variant Curation Expert Panel	reviewed by expert panel (ClinGen PAH ACMG Specifications v1)	Uncertain significance (Jan 25, 2020)	germline	curation	Citation Link,
SCV001374395	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 4, 2019)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 14722928, 25894915, 23430918, 17096675, 26666653, 19292873, 18985011, 1709636, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000143852

Inserm U 954, Faculté de Médecine de Nancy

no assertion criteria provided

probable-pathogenic

unknown

not provided

SCV001250558

ClinGen PAH Variant Curation Expert Panel

reviewed by expert panel

(ClinGen PAH ACMG Specifications v1)

Uncertain significance
(Jan 25, 2020)

germline

curation

Citation Link,

SCV001374395

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 4, 2019)

germline

clinical testing

PubMed (9)
[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
not provided	not provided	not provided	not provided	not provided	not provided	1	not provided	literature only

Citations

PubMed

Mutation spectrum in Taiwanese patients with phenylalanine hydroxylase deficiency and a founder effect for the R241C mutation.

Chien YH, Chiang SC, Huang A, Chou SP, Tseng SS, Huang YT, Hwu WL.

Hum Mutat. 2004 Feb;23(2):206. doi: 10.1002/humu.9215.

PubMed [citation]

PMID:: 14722928

Mutational spectrum of phenylketonuria in Jiangsu province.

Chen YF, Jia HT, Chen ZH, Song JP, Liang Y, Pei JJ, Wu ZJ, Wang J, Qiu YL, Liu G, Sun DM, Jiang XY.

Eur J Pediatr. 2015 Oct;174(10):1333-8. doi: 10.1007/s00431-015-2539-z. Epub 2015 Apr 19.

PubMed [citation]

PMID:: 25894915

See all PubMed Citations (9)

Details of each submission

From Inserm U 954, Faculté de Médecine de Nancy, SCV000143852.1

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

Description

Converted during submission to Likely pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	not provided	1	not provided	not provided		not provided	not provided	not provided	not provided

From ClinGen PAH Variant Curation Expert Panel, SCV001250558.1

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

Description

The c.284_285delTCinsCA (p.Ile95Thr) indel variant in PAH has not been reported in the literature to our knowledge. It has been included in BioPKU/PAHdb (PAH0793) by online submission (Namour et al.,2013). It is absent from ExAC, gnomAD, 1000G, and ESP. There is not consensus among predictions of pathogenicity. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2.

#	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, SCV001374395.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

This sequence change replaces isoleucine with threonine at codon 95 of the PAH protein (p.Ile95Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with PAH-related conditions. ClinVar contains an entry for this variant (Variation ID: 120272). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). This variant disrupts the p.Ile95 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14722928, 1709636, 17096675, 18985011, 19292873, 23430918, 25894915, 26666653). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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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