NM_000277.3(PAH):c.960G>C (p.Lys320Asn) AND Phenylketonuria

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Oct 25, 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:: RCV000666332.13

Allele description [Variation Report for NM_000277.3(PAH):c.960G>C (p.Lys320Asn)]

NM_000277.3(PAH):c.960G>C (p.Lys320Asn)

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.960G>C (p.Lys320Asn)

HGVS:

NC_000012.12:g.102846904C>G
NG_008690.2:g.116507G>C
NM_000277.3:c.960G>CMANE SELECT
NM_001354304.2:c.960G>C
NP_000268.1:p.Lys320Asn
NP_001341233.1:p.Lys320Asn
NC_000012.11:g.103240682C>G
NM_000277.1:c.960G>C

Protein change:

K320N

Links:

dbSNP: rs199475615

NCBI 1000 Genomes Browser:

rs199475615

Molecular consequence:

NM_000277.3:c.960G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354304.2:c.960G>C - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000790605	Counsyl	no assertion criteria provided	Likely pathogenic (Oct 9, 2017)	unknown	clinical testing	PubMed (9) [See all records that cite these PMIDs] 12655553, 24350308, 17924342, 12655554, 8659548, 18590700, 11678552, 23764561, 23062575
SCV001391599	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Feb 24, 2024)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 8659548, 11678552, 12655553, 12655554, 23764561, 24350308, 28492532
SCV002499656	Institute of Human Genetics, University Hospital Muenster	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 31, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004201979	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 5, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005422074	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Oct 25, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 8659548, 32668217, 33101986 Citation Link

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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Predicted effects of missense mutations on native-state stability account for phenotypic outcome in phenylketonuria, a paradigm of misfolding diseases.

Pey AL, Stricher F, Serrano L, Martinez A.

Am J Hum Genet. 2007 Nov;81(5):1006-24. Epub 2007 Oct 2.

PubMed [citation]

PMID:: 17924342
PMCID:: PMC2265664

Simultaneous assessment of the effects of exonic mutations on RNA splicing and protein functions.

Ho PY, Huang MZ, Fwu VT, Lin SC, Hsiao KJ, Su TS.

Biochem Biophys Res Commun. 2008 Sep 5;373(4):515-20. doi: 10.1016/j.bbrc.2008.06.072. Epub 2008 Jun 30.

PubMed [citation]

PMID:: 18590700

See all PubMed Citations (13)

Details of each submission

From Counsyl, SCV000790605.2

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

#	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, SCV001391599.6

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

Description

This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 320 of the PAH protein (p.Lys320Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with PAH-related conditions (PMID: 8659548, 11678552, 12655553, 12655554, 23764561, 24350308; Invitae). ClinVar contains an entry for this variant (Variation ID: 102910). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PAH protein function with a negative predictive value of 80%. 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 Institute of Human Genetics, University Hospital Muenster, SCV002499656.2

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

Description

ACMG categories: PS5,PM3,PM7,PP1,PP3,PP5

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

From Baylor Genetics, SCV004201979.2

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005422074.1

#	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.960G>C (p.Lys320Asn) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain (IPR019774) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251278 control chromosomes. c.960G>C has been reported in the literature in multiple compound heterozygous individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (Guldberg_1996, Hillert_2020, Kreile_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 8659548, 32668217, 33101986). ClinVar contains an entry for this variant (Variation ID: 102910). 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

Last Updated: Apr 13, 2025

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