NM_000277.3(PAH):c.281TCA[1] (p.Ile95del) AND Phenylketonuria

Germline classification:: Pathogenic (11 submissions)
Last evaluated:: Oct 18, 2019
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:: RCV000000635.97

Allele description [Variation Report for NM_000277.3(PAH):c.281TCA[1] (p.Ile95del)]

NM_000277.3(PAH):c.281TCA[1] (p.Ile95del)

Gene:

PAH:phenylalanine hydroxylase [Gene - OMIM - HGNC]

Variant type:

Microsatellite

Cytogenetic location:

12q23.2

Genomic location:

Preferred name:

NM_000277.3(PAH):c.281TCA[1] (p.Ile95del)

HGVS:

NC_000012.12:g.102894801_102894803delTGA
NC_000012.12:g.102894803ATG[1]
NG_008690.2:g.68605TCA[1]
NM_000277.3:c.281TCA[1]MANE SELECT
NM_000277.3:c.284_286del
NM_001354304.2:c.281TCA[1]
NP_000268.1:p.Ile95del
NP_001341233.1:p.Ile95del
NC_000012.11:g.103288579_103288581del
NC_000012.11:g.103288581ATG[1]
NC_000012.12:g.102894801_102894803delTGA
NC_000012.12:g.102894803_102894805ATG[1]
NM_000277.1:c.283_285delATC
NM_000277.1:c.284_286delTCA
NM_000277.3(PAH):c.281_283TCA[1]MANE SELECT
NM_000277.3:c.284_286delMANE SELECT
NM_000277.3:c.284_286delTCAMANE SELECT
p.I95del

Protein change:

I95del

Links:

OMIM: 612349.0030; dbSNP: rs62508727

NCBI 1000 Genomes Browser:

rs62508727

Molecular consequence:

NM_000277.3:c.281TCA[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001354304.2:c.281TCA[1] - inframe_deletion - [Sequence Ontology: SO:0001822]

Observations:

Condition(s)

Name:: Phenylketonuria (PKU)
Synonyms:: FOLLING DISEASE; OLIGOPHRENIA PHENYLPYRUVICA; Phenylketonurias
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
SCV000020785	OMIM	no assertion criteria provided	Pathogenic (Aug 15, 2007)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 1709636, 17630668
SCV000485292	Counsyl	no assertion criteria provided	Likely pathogenic (May 19, 2016)	unknown	clinical testing	PubMed (12) [See all records that cite these PMIDs] 20457534, 24705691, 1709636, 20217238, 16256386, 19292873, 23430918, 14722928, 25894915, 17096675, 18985011, 24368688
SCV000629189	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 27, 2024)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 1709636, 14722928, 17096675, 18985011, 19292873, 23430918, 25894915, 26666653, 28492532
SCV001250569	ClinGen PAH Variant Curation Expert Panel	reviewed by expert panel (ClinGen PAH ACMG Specifications v1)	Pathogenic (Oct 18, 2019)	germline	curation	PubMed (10) [See all records that cite these PMIDs] 29316886, 25894915, 24368688, 30747360, 30050108, 26666653, 19292873, 29560316, 18985011, 26503515 Citation Link,
SCV001251471	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill - NSIGHT-NC NEXUS	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	research	PubMed (7) [See all records that cite these PMIDs] 20301677, 1709636, 18985011, 19292873, 25894915, 26666653, 25741868
SCV001372242	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jun 15, 2020)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 17096675, 1709636, 14722928 Citation Link,
SCV001455112	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV004201357	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 16, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004847268	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 6, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005061252	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 22, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005416622	Juno Genomics, Hangzhou Juno Genomics, Inc	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing, research
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Phenylalanine hydroxylase deficiency exhibits mutation heterogeneity in two large old order Amish settlements.

Wang H, Nye L, Puffenberger E, Morton H.

Am J Med Genet A. 2007 Aug 15;143A(16):1938-40. No abstract available.

PubMed [citation]

PMID:: 17630668

The phenylalanine hydroxylase c.30C>G synonymous variation (p.G10G) creates a common exonic splicing silencer.

Dobrowolski SF, Andersen HS, Doktor TK, Andresen BS.

Mol Genet Metab. 2010 Aug;100(4):316-23. doi: 10.1016/j.ymgme.2010.04.002. Epub 2010 Apr 14.

PubMed [citation]

PMID:: 20457534

See all PubMed Citations (22)

Details of each submission

From OMIM, SCV000020785.66

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

In a patient with mild phenylketonuria (PKU; 261600), Caillaud et al. (1991) reported a 3-bp in-frame deletion resulting in loss of isoleucine-94. The mutant enzyme showed markedly reduced affinity for phenylalanine. Since the deletion was located in the third exon of the gene, which shows no homology with other hydroxylases, Caillaud et al. (1991) suggested that exon 3 is involved in the specificity of PAH for phenylalanine. It appeared that this mutation may have occurred recently on the background of a haplotype II gene in Portugal.

In patients with PKU from the Old Order Amish in Lancaster County, Pennsylvania, Wang et al. (2007) identified compound heterozygosity for 2 PAH mutations: R261Q (612349.0006) and the 3-bp deletion at codon 94. The incidence of PKU in the Lancaster County Amish was 1 in 10,000, similar to that in other populations.

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

From Counsyl, SCV000485292.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (12)

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000629189.10

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

Description

This variant, c.284_286del, results in the deletion of 1 amino acid(s) of the PAH protein (p.Ile95del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs62508727, gnomAD 0.006%). This variant has been observed in individual(s) with phenylketonuria and hyperphenylalaninemia (PMID: 1709636, 14722928, 17096675, 18985011, 19292873, 23430918, 25894915, 26666653). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Ile94del. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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

From ClinGen PAH Variant Curation Expert Panel, SCV001250569.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (10)

Description

This variant was documented in 8 patients diagnosed with PAH deficiency (PMID: 26503515, 30747360, 30050108, 29560316, 18985011). Tetrahydrobiopterin (BH4) deficiency was excluded through a BH4 loading test, urinary pterin analysis, and DHPR activity assay. This variant was detected in trans with a pathogenic or likely pathogenic PAH variant in 2 patients with PKU and 3 patients with hyperphenylalaninemia (PMID: 19292873, 24368688, 25894915, 26666653, 29316886). This variant is present at a frequency below 0.0002 in the population databases ExAC and gnomAD. This variant changes protein length from an in-frame deletion in a non-repeat region. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PM4, PP4_moderate.

#	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 UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill - NSIGHT-NC NEXUS, SCV001251471.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	research	PubMed (7)

Description

The PAH c.284_286delTCA (p.I95del) variant results in a deletion of a single amino acid and has been observed in homozygous and compound heterozygous state in individuals with phenylketonuria. This variant has previously been shown to result in a reduced affinity of the PAH enzyme for phenylalanine (PMID: 1709636; 18985011; 19292873; 25894915; 26666653).

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001372242.1

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

Description

Variant summary: PAH c.284_286delTCA (p.Ile95del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 2e-05 in 251448 control chromosomes. c.284_286delTCA has been well reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (example, Chien_2004, Daniele_2007, Caillaud_1991). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal enzyme activity (Maximal velocity/Km) due to a markedly decreased subtrate specificity (increased Km) for Phenylalanine (Caillaud_1991). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=4)/likely pathogenic(n=1). Based on the evidence outlined above, the variant was 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

From Natera, Inc., SCV001455112.1

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

#	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 Baylor Genetics, SCV004201357.2

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004847268.1

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

Description

The p.Ile95del variant in PAH has been reported, in the homozygous and compound heterozygous state, in numerous (at least 10) individuals with PAH deficiency (phenylketonuria or hyperphenylalaninemia) (Li 2015 PMID: 26503515, Yan 2019 PMID: 30747360, Li 2008 PMID: 30050108, Schwoerer 2018 PMID: 29560316, Lee 2008 PMID: 18985011, Daniele 2009 PMID: 19292873, Ho 2014 PMID: 24368688, Chen 2015 PMID: 25894915, Jeannesson-Thivisol 2015 PMID: 26666653, Liu 2018 PMID: 29316886). It has also been classified as pathogenic on Oct 18, 2019 by the ClinGen PAH Variant Curation Expert Panel (Variation ID 604) and has been identified in 13/912 Amish and 5/68036 European chromosomes by gnomAD (https://gnomad.broadinstitute.org/). This variant is a deletion of 1 amino acid at position 95 and is not predicted to alter the protein reading-frame. In vitro functional studies support an impact on protein function as they show it results in a reduced affinity of the PAH enzyme for phenylalanine (Caillaud 1991 PMID: 1709636). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive phenylalanine hydroxylase (PAH) deficiency. ACMG/AMP criteria applied: PM3_Very strong, PM2_Supporting, PM4, PS3_Moderate.

#	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 Neuberg Centre For Genomic Medicine, NCGM, SCV005061252.2

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

Description

The inframe deletion variant c.284_286del (p.Ile95del) in PAH gene has been reported previously in multiple individuals affected with phenylketonuria (Schwoerer et al. 2018; Yan et al. 2019). In vitro expression studies showed that this variant produced very low levels of PAH activity (Li et al. 2015). The p.Ile95del variant is present with an allele frequency of 0.002% in the gnomAD exomes database. This variant has been submitted to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submissions). This p.Ile95del causes deletion of amino acid Isoleucine at position 95. For these reasons, this variant has been classified as Pathogenic. The observed variant in PAH gene is absent in spouse.

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

From Juno Genomics, Hangzhou Juno Genomics, Inc, SCV005416622.1

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

Description

PM2_Supporting+PM4+PM3_VeryStrong

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

Last Updated: Feb 25, 2025

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