NM_000277.3(PAH):c.47_48del (p.Leu15_Ser16insTer) AND Phenylketonuria

Germline classification:: Pathogenic (9 submissions)
Last evaluated:: Aug 10, 2018
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:: RCV000153638.25

Allele description [Variation Report for NM_000277.3(PAH):c.47_48del (p.Leu15_Ser16insTer)]

NM_000277.3(PAH):c.47_48del (p.Leu15_Ser16insTer)

Gene:

PAH:phenylalanine hydroxylase [Gene - OMIM - HGNC]

Variant type:

Microsatellite

Cytogenetic location:

12q23.2

Genomic location:

Preferred name:

NM_000277.3(PAH):c.47_48del (p.Leu15_Ser16insTer)

Other names:

NM_000277.2(PAH):c.47_48delCT

HGVS:

NC_000012.12:g.102917083AG[2]
NG_008690.2:g.46323CT[2]
NM_000277.3:c.47_48delMANE SELECT
NM_001354304.2:c.47_48del
NP_000268.1:p.Leu15_Ser16insTer
NP_001341233.1:p.Leu15_Ser16insTer
NC_000012.11:g.103310861AG[2]
NC_000012.11:g.103310861_103310862del
NC_000012.12:g.102917083_102917084delAG
NM_000277.1:c.47_48del
NM_000277.1:c.47_48delCT
NM_000277.3:c.47_48delCTMANE SELECT

Links:

dbSNP: rs62642906

NCBI 1000 Genomes Browser:

rs62642906

Molecular consequence:

NM_000277.3:c.47_48del - nonsense - [Sequence Ontology: SO:0001587]
NM_001354304.2:c.47_48del - nonsense - [Sequence Ontology: SO:0001587]

Observations:

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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Rattus norvegicus ADCYAP receptor type I (Adcyap1r1), transcript variant 2, mRNA
Rattus norvegicus ADCYAP receptor type I (Adcyap1r1), transcript variant 2, mRNA
gi|396080324|ref|NM_133511.2|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000221085	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Jan 26, 2015)	unknown	literature only	PubMed (11) [See all records that cite these PMIDs] 19444284, 17935162, 8535445, 10394930, 12655553, 12655550, 23430547, 21147011, 16879198, 19062537, 23357515 Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015), Citation Link,
SCV000754077	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 21, 2023)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 1301187, 9634518, 8535445, 10394930, 16198137, 17096675, 21147011, 21890392, 26322415, 28492532
SCV000852108	ClinGen PAH Variant Curation Expert Panel	reviewed by expert panel (ClinGen PAH ACMG Specifications v1)	Pathogenic (Aug 10, 2018)	germline	curation	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001362289	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Mar 25, 2019)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 26322415, 26210745, 7726156, 29176022 Citation Link,
SCV001459232	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV002107119	DASA	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 5, 2022)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 8535445, 10394930, 16198137, 17096675, 21147011, 21890392, 26322415, 25741868
SCV004099308	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	no assertion criteria provided	Pathogenic (Oct 30, 2023)	germline	clinical testing
SCV004201315	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 26, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004800848	Neonatal Disease Screening Center, Medical Genetics Center, Huaihua City Maternal and Child Health Care Hospital	no assertion criteria provided (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing

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
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, literature only
Han	germline	yes	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

A limited spectrum of phenylalanine hydroxylase mutations is observed in phenylketonuria patients in western Poland and implications for treatment with 6R tetrahydrobiopterin.

Dobrowolski SF, Borski K, Ellingson CC, Koch R, Levy HL, Naylor EW.

J Hum Genet. 2009 Jun;54(6):335-9. doi: 10.1038/jhg.2009.37. Epub 2009 May 15.

PubMed [citation]

PMID:: 19444284

Molecular genetics of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency.

Zurflüh MR, Zschocke J, Lindner M, Feillet F, Chery C, Burlina A, Stevens RC, Thöny B, Blau N.

Hum Mutat. 2008 Jan;29(1):167-75.

PubMed [citation]

PMID:: 17935162

See all PubMed Citations (22)

PMC

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Details of each submission

From Counsyl, SCV000221085.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (11)

#	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, SCV000754077.4

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

Description

This sequence change creates a premature translational stop signal (p.Ser16*) in the PAH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518). This variant is present in population databases (rs62642906, gnomAD 0.0009%). This premature translational stop signal has been observed in individuals with hyperphenylalaninemia and phenylketonuria (PMID: 8535445, 10394930, 16198137, 17096675, 21147011, 21890392, 26322415). This variant is also known as c.44_45delTC, p.Ser16fs. ClinVar contains an entry for this variant (Variation ID: 102696). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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, SCV000852108.4

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

Description

PAH-specific ACMG/AMP criteria applied: PM2: ExAC:8.238e-06; gnomAD:0.000004062; 1000G + ESP: absent; PVS1: Null variant- frameshift. Subject to nonsense mediated decay.; PM3: found in trans with L48S (VarID608, Pathogenic) (PMID:8535445); PP4: 47delCT found in 1 patient with moderate PKU. BH4 deficiency not ruled out. (PMID:8535445). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PVS1, PM3, PP4).

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001362289.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Variant summary: PAH c.47_48delCT (p.Ser16X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (c.165delT, p.Phe55fsX6; c.331C>T, p.Arg111X; c.556delA, p.Thr186fsX9). The variant allele was found at a frequency of 4.1e-06 in 246214 control chromosomes (gnomAD). This variant has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Aldamiz-Echevarria_2016, Ramus_1995, Tao_2015, Trunzo_2015, Wang_2017). These data indicate that the variant is very likely to be associated with disease. In vitro expression experiment reports that PAH residual activity for this variant effect results in <10% of normal activity (Aldamiz-Echevarria_2016). Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely pathogenic/pathogenic. 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., SCV001459232.1

#	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 DASA, SCV002107119.2

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

Description

The c.47_48delCT;p.(Ser16*) variant creates a premature translational stop signal in the PAH gene. It is expected to result in an absent or disrupted protein product - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 10269; PMID: 8535445; PMID: 10394930; PMID: 16198137; PMID: 17096675; PMID: 21147011; PMID: 21890392; PMID: 263224156) - PS4. This variant is not present in population databases (rs62642906- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The p.(Ser16*) was detected in trans with a pathogenic variant (PMID:8535445) - PM3. In summary, the currently available evidence indicates that the variant is pathogenic.

#	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 Zotz-Klimas Genetics Lab, MVZ Zotz Klimas, SCV004099308.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004201315.2

#	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 Neonatal Disease Screening Center, Medical Genetics Center, Huaihua City Maternal and Child Health Care Hospital, SCV004800848.1

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

Description

PVS1+PM2+PM3_S+PP4_M

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

Last Updated: Sep 29, 2024

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