NM_000277.3(PAH):c.1042C>G (p.Leu348Val) AND not provided

Germline classification:: Pathogenic (7 submissions)
Last evaluated:: Jan 1, 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:: RCV000078498.40

Allele description [Variation Report for NM_000277.3(PAH):c.1042C>G (p.Leu348Val)]

NM_000277.3(PAH):c.1042C>G (p.Leu348Val)

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.1042C>G (p.Leu348Val)

HGVS:

NC_000012.12:g.102844359G>C
NG_008690.2:g.119052C>G
NM_000277.3:c.1042C>GMANE SELECT
NM_001354304.2:c.1042C>G
NP_000268.1:p.Leu348Val
NP_000268.1:p.Leu348Val
NP_001341233.1:p.Leu348Val
NC_000012.11:g.103238137G>C
NM_000277.1:c.1042C>G
P00439:p.Leu348Val

Protein change:

L348V

Links:

UniProtKB: P00439#VAR_001012; dbSNP: rs62516092

NCBI 1000 Genomes Browser:

rs62516092

Molecular consequence:

NM_000277.3:c.1042C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354304.2:c.1042C>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

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MAG: DNA repair protein RecO [Firmicutes bacterium ADurb.Bin373]
MAG: DNA repair protein RecO [Firmicutes bacterium ADurb.Bin373]
gi|1167172117|gb|OQA11385.1||gnl|WG S|BWY65_00019

Protein
Mus musculus gremlin 1, DAN family BMP antagonist (Grem1), mRNA
Mus musculus gremlin 1, DAN family BMP antagonist (Grem1), mRNA
gi|215490119|ref|NM_011824.4|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000110354	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Pathogenic (May 20, 2014)	germline	clinical testing	Citation Link,
SCV000119300	DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	no classification provided	not provided	not provided	not provided
SCV000490682	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Feb 10, 2020)	germline	clinical testing	Citation Link,
SCV000601705	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Jul 13, 2023)	unknown	clinical testing	PubMed (30) [See all records that cite these PMIDs] 31623983, 31355225, 30037505, 26666653, 24190797, 24350308, 23500595, 23430918, 22841515, 21953985, 20082265, 15464430, 12655553, 11524738, 11385716, 11180595, 10679941, 9012412, 8632937, 8533759, 1301187, 30648773, 33375644, 33465300, 34828281, 10479481, 25596310, 17935162, 18937047, 26467025
SCV001249173	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Jan 1, 2024)	germline	clinical testing	Citation Link,
SCV001927990	Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001958196	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	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	4	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	23	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

Citations

PubMed

Phenylalanine hydroxylase genotype-phenotype associations in the United States: A single center study.

Rajabi F, Rohr F, Wessel A, Martell L, Dobrowolski SF, Guldberg P, Güttler F, Levy HL.

Mol Genet Metab. 2019 Dec;128(4):415-421. doi: 10.1016/j.ymgme.2019.09.004. Epub 2019 Sep 14.

PubMed [citation]

PMID:: 31623983

The molecular epidemiology of hyperphenylalaninemia in Uygur population: incidence from newborn screening and mutational spectra.

Su Y, Wang H, Rejiafu N, Wu B, Jiang H, Chen H, A X, Qian Y, Li M, Lu Y, Ren Y, Li L, Zhou W.

Ann Transl Med. 2019 Jun;7(12):258. doi: 10.21037/atm.2019.05.16.

PubMed [citation]

PMID:: 31355225
PMCID:: PMC6614323

See all PubMed Citations (30)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000110354.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	23	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		23	not provided	not provided	not provided

From DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE, SCV000119300.1

#	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, SCV000490682.3

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

Description

Functional studies report the in vitro phenylalanine hydroxylase activity associated with L348V as 25-44% of wild type (Couce et al., 2013; Zurfluh et al., 2008; Pey et al., 2007), and that the mutant enzyme showed a substantial reduction in binding affinity for BH4, but stabilization by BH4 was similar to wild type (Dobrowolski et al., 2009); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Responsiveness to BH4 therapy is not clear (Zurflh et al., 2008; Dobrowolski et al., 2009; Aldmiz-Echevarra et al., 2016).; This variant is associated with the following publications: (PMID: 25750018, 10479481, 25087612, 18937047, 25596310, 21953985, 17924342, 17935162, 23500595, 28850634, 29102225, 30037505, 30648773, 31355225, 1301187, 27121329, 31589614, 32668217)

#	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 Quest Diagnostics Nichols Institute San Juan Capistrano, SCV000601705.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (30)

Description

The PAH c.1042C>G (p.Leu348Val) variant has been reported in the published literature in multiple individuals affected with classical phenylketonuria or mild hyperphenylalaninemia (PMIDs: 8632937 (1996), 9012412 (1997), 18937047 (2009), 26666653 (2015), 31355225 (2019), 33375644 (2020), 34828281 (2021)). Functional studies show that this variant is destabilizing, though improvement was observed with tetrahydrobiopterin (BH4) treatment (PMID: 30648773 (2019)). The variant was also reported to have lower BH4 binding affinity (PMID: 18937047 (2009)). In addition, the variant had a PAH activity range of 8-41% of the wild-type in vitro (PMIDs: 10479481 (1999), 17935162 (2008), 25596310 (2015), 30037505 (2018)). The frequency of this variant in the general population, 0.00043 (22/50764 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.

#	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 CeGaT Center for Human Genetics Tuebingen, SCV001249173.26

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

Description

PAH: PM3:Very Strong, PS3, PM2, PP4:Moderate, PP3

#	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		4	not provided	not provided	not provided

From Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus, SCV001927990.1

#	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 Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001958196.1

#	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

Last Updated: Nov 3, 2024

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