NM_000277.3(PAH):c.143T>C (p.Leu48Ser) AND not provided

Germline classification:: Pathogenic (6 submissions)
Last evaluated:: Aug 14, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000078511.43

Allele description [Variation Report for NM_000277.3(PAH):c.143T>C (p.Leu48Ser)]

NM_000277.3(PAH):c.143T>C (p.Leu48Ser)

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.143T>C (p.Leu48Ser)

Other names:

p.L48S:TTG>TCG

HGVS:

NC_000012.12:g.102912816A>G
NG_008690.2:g.50595T>C
NM_000277.3:c.143T>CMANE SELECT
NM_001354304.2:c.143T>C
NP_000268.1:p.Leu48Ser
NP_000268.1:p.Leu48Ser
NP_001341233.1:p.Leu48Ser
NC_000012.11:g.103306594A>G
NM_000277.1:c.143T>C
NM_000277.2(PAH):c.143T>C
P00439:p.Leu48Ser
c.143T>C (p.Leu48Ser)

Protein change:

L48S; LEU48SER

Links:

UniProtKB: P00439#VAR_000877; OMIM: 612349.0034; dbSNP: rs5030841

NCBI 1000 Genomes Browser:

rs5030841

Molecular consequence:

NM_000277.3:c.143T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354304.2:c.143T>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000110367	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Pathogenic (Dec 13, 2012)	germline	clinical testing	Citation Link,
SCV000119432	DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	no classification provided	not provided	not provided	not provided
SCV000239058	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Aug 14, 2024)	germline	clinical testing	Citation Link,
SCV000280706	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 29, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001250401	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Mar 1, 2024)	germline	clinical testing	Citation Link,
SCV002774366	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Oct 12, 2021)	unknown	clinical testing	PubMed (9) [See all records that cite these PMIDs] 25596310, 17935162, 21953985, 23500595, 33465300, 1679030, 16879198, 23430547, 26467025

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	14	not provided	not provided	not provided	not provided	clinical testing
not provided	not provided	not provided	not provided	not provided	not provided	1	not provided	literature only
not provided	germline	yes	8	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Mapping the functional landscape of frequent phenylalanine hydroxylase (PAH) genotypes promotes personalised medicine in phenylketonuria.

Danecka MK, Woidy M, Zschocke J, Feillet F, Muntau AC, Gersting SW.

J Med Genet. 2015 Mar;52(3):175-85. doi: 10.1136/jmedgenet-2014-102621. Epub 2015 Jan 16.

PubMed [citation]

PMID:: 25596310

See all PubMed Citations (10)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000110367.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	14	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		14	not provided	not provided	not provided

From DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE, SCV000119432.1

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

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

From GeneDx, SCV000239058.15

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

Description

Functional studies demonstrate p.(L48S) is associated with significantly reduced enzyme activity compared to wildtype (PMID: 25596310, 26803807); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21953985, 25525159, 1679030, 30963030, 34900593, 23500595, 25087612, 11461190, 17935162, 23559577, 22975760, 23430547, 26803807, 9323556, 28676969, 9399896, 31355225, 26322415, 16879198, 34426522, 31589614, 33101986, 8592329, 32778825, 33465300, 36537053, 36646061, 36672771, 35405047, 25596310, 37189584)

#	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 Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics, SCV000280706.2

#	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	germline	not provided	not provided	not provided	not provided		not provided	0.000555	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV001250401.26

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

Description

PAH: PM3:Very Strong, PM2, PP4:Moderate, PS3:Supporting

#	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		8	not provided	not provided	not provided

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV002774366.1

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

Description

This variant is associated with a variable phenotype that ranges from hyperphenylalaninemia to classic PKU (PMIDs: 25596310 (2015), 23430547 (2013), 21953985 (2012), 16879198 (2006), and 1679030 (1991)). The variant occurs in multiple cases with a lone recessive pathogenic/likely pathogenic variant in the same gene, and several have a phenotype known to be consistent with disease. In addition, experimental studies have shown that this variant has deleterious effects on PAH enzyme activity and protein expression (PMIDs: 25596310 (2015), 23500595 (2013), 21953985 (2012), and 17935162 (2008)).

#	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

Last Updated: Nov 3, 2024

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