NM_000277.3(PAH):c.344_347del (p.Lys115fs) AND Phenylketonuria

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Oct 14, 2022
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:: RCV001175457.2

Allele description [Variation Report for NM_000277.3(PAH):c.344_347del (p.Lys115fs)]

NM_000277.3(PAH):c.344_347del (p.Lys115fs)

Gene:

PAH:phenylalanine hydroxylase [Gene - OMIM - HGNC]

Variant type:

Microsatellite

Cytogenetic location:

12q23.2

Genomic location:

Preferred name:

NM_000277.3(PAH):c.344_347del (p.Lys115fs)

Other names:

NM_000277.3(PAH):c.344_347del; p.Lys115fs

HGVS:

NC_000012.12:g.102894740TCTT[1]
NG_008690.2:g.68664AAGA[1]
NM_000277.3:c.344_347delMANE SELECT
NM_001354304.2:c.344_347del
NP_000268.1:p.Lys115fs
NP_001341233.1:p.Lys115fs
NC_000012.11:g.103288518TCTT[1]
NM_000277.1:c.344_347delAAGA

Protein change:

K115fs

Links:

dbSNP: rs199475648

NCBI 1000 Genomes Browser:

rs199475648

Molecular consequence:

NM_000277.3:c.344_347del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354304.2:c.344_347del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Phenylketonuria (PKU)
Synonyms:: Phenylketonurias; Oligophrenia phenylpyruvica; Folling disease
Identifiers:: MONDO: MONDO:0009861; MedGen: C0031485; Orphanet: 716; OMIM: 261600

Recent activity

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SHC-transforming protein 1 isoform 2 [Homo sapiens]
SHC-transforming protein 1 isoform 2 [Homo sapiens]
gi|32261324|ref|NP_003020.2|

Protein
segment polarity protein dishevelled homolog DVL-2 [Homo sapiens]
segment polarity protein dishevelled homolog DVL-2 [Homo sapiens]
gi|4758216|ref|NP_004413.1|

Protein
ras-related protein Rab-7b isoform a [Homo sapiens]
ras-related protein Rab-7b isoform a [Homo sapiens]
gi|256985158|ref|NP_796377.3|

Protein
RecName: Full=NHP2-like protein 1; AltName: Full=High mobility group-like nuclea...
RecName: Full=NHP2-like protein 1; AltName: Full=High mobility group-like nuclear protein 2 homolog 1; AltName: Full=OTK27; AltName: Full=SNU13 homolog; Short=hSNU13; AltName: Full=U4/U6.U5 small nuclear ribonucleoprotein SNU13; AltName: Full=U4/U6.U5 tri-snRNP 15.5 kDa protein; Contains: RecName: Full=NHP2-like protein 1, N-terminally processed
gi|2500345|sp|P55769.3|NH2L1_HUMAN

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001339027	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Mar 1, 2020)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 28676969, 11207989 Citation Link,
SCV002818520	ClinGen PAH Variant Curation Expert Panel	reviewed by expert panel (ClinGen PAH ACMG Specifications v1)	Pathogenic (Oct 14, 2022)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001339027

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Mar 1, 2020)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV002818520

ClinGen PAH Variant Curation Expert Panel

reviewed by expert panel

(ClinGen PAH ACMG Specifications v1)

Pathogenic
(Oct 14, 2022)

germline

curation

Citation Link

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

Citations

PubMed

Genetic study of the PAH locus in the Iranian population: familial gene mutations and minihaplotypes.

Razipour M, Alavinejad E, Sajedi SZ, Talebi S, Entezam M, Mohajer N, Kazemi-Sefat GE, Gharesouran J, Setoodeh A, Mohaddes Ardebili SM, Keramatipour M.

Metab Brain Dis. 2017 Oct;32(5):1685-1691. doi: 10.1007/s11011-017-0048-7. Epub 2017 Jul 4.

PubMed [citation]

PMID:: 28676969

Mutation analysis of phenylketonuria in Yamagata prefecture, Japan.

Kimura T, Ikeda H, Akaba K, Guldberg P, Güttler F, Maki K, Aikawa S, Hayasaka K.

Pediatr Int. 2001 Feb;43(1):1-3.

PubMed [citation]

PMID:: 11207989

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001339027.1

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

Description

Variant summary: PAH c.344_347delAAGA (p.Lys115ThrfsX79) 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. The variant was absent in 251430 control chromosomes. c.344_347delAAGA has been reported in the literature in individuals from diverse ethnicities affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (example, Kimura_2001, Razipour_2017) and has been subsequently cited by others. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. 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 ClinGen PAH Variant Curation Expert Panel, SCV002818520.1

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

Description

This c.344_347del (p.Lys115fs) variant in PAH was detected with the c.1315+1G>A pathogenic variant and the c.1066-14C>G likely pathogenic variant in multiple patients with PKU, phasing was not available (PMID: 11207989, 28676969, 25551302). This variant was absent in population databases. This is a frameshift variant in exon 3 of 13 coding exons with termination at position 194 predicted to undergo nonsense mediated decay. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3_Supporting, 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

Last Updated: Jan 21, 2023

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