NM_000277.3(PAH):c.1187A>G (p.Lys396Arg) AND Phenylketonuria

Germline classification:: Likely pathogenic (3 submissions)
Last evaluated:: Aug 13, 2020
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:: RCV001236942.10

Allele description [Variation Report for NM_000277.3(PAH):c.1187A>G (p.Lys396Arg)]

NM_000277.3(PAH):c.1187A>G (p.Lys396Arg)

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.1187A>G (p.Lys396Arg)

HGVS:

NC_000012.12:g.102843658T>C
NG_008690.2:g.119753A>G
NM_000277.3:c.1187A>GMANE SELECT
NM_001354304.2:c.1187A>G
NP_000268.1:p.Lys396Arg
NP_001341233.1:p.Lys396Arg
NC_000012.11:g.103237436T>C
NM_000277.1:c.1187A>G

Protein change:

K396R

Links:

dbSNP: rs776178623

NCBI 1000 Genomes Browser:

rs776178623

Molecular consequence:

NM_000277.3:c.1187A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354304.2:c.1187A>G - missense variant - [Sequence Ontology: SO:0001583]

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001409683	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 27, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 21147011, 23357515, 28492532
SCV002032194	ClinGen PAH Variant Curation Expert Panel	reviewed by expert panel (ClinGen PAH ACMG Specifications v1)	Likely pathogenic (Aug 13, 2020)	germline	curation	Citation Link,
SCV004209663	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 29, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001409683

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 27, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV002032194

ClinGen PAH Variant Curation Expert Panel

reviewed by expert panel

(ClinGen PAH ACMG Specifications v1)

Likely pathogenic
(Aug 13, 2020)

germline

curation

Citation Link,

SCV004209663

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(May 29, 2023)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

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

Citations

PubMed

Molecular genetics and impact of residual in vitro phenylalanine hydroxylase activity on tetrahydrobiopterin responsiveness in Turkish PKU population.

Dobrowolski SF, Heintz C, Miller T, Ellingson C, Ellingson C, Ozer I, Gökçay G, Baykal T, Thöny B, Demirkol M, Blau N.

Mol Genet Metab. 2011 Feb;102(2):116-21. doi: 10.1016/j.ymgme.2010.11.158. Epub 2010 Nov 18.

PubMed [citation]

PMID:: 21147011

Hyperphenylalaninemia in the Czech Republic: genotype-phenotype correlations and in silico analysis of novel missense mutations.

Réblová K, Hrubá Z, Procházková D, Pazdírková R, Pouchlá S, Zeman J, Fajkusová L.

Clin Chim Acta. 2013 Apr 18;419:1-10. doi: 10.1016/j.cca.2013.01.006. Epub 2013 Jan 26. Erratum in: Clin Chim Acta. 2013 Nov 15;426:157. Zeman, Jiří [added].

PubMed [citation]

PMID:: 23357515

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001409683.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 396 of the PAH protein (p.Lys396Arg). This variant is present in population databases (rs776178623, gnomAD 0.003%). This missense change has been observed in individual(s) with phenylketonuria (PMID: 21147011, 23357515). ClinVar contains an entry for this variant (Variation ID: 962987). 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. 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, SCV002032194.1

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

Description

The c.1187A>G (p.Lys396Arg) variant in PAH has been reported in multiple individuals with mild HPA and PKU (BH4 deficiency excluded). (PMID: 21147011, 23357515). This variant has extremely low frequency in ExAC and gnomAD (MAF=0.00006). This variant was detected with pathogenic variants IVS10-11G>A in 2 patients (PMID: 21147011) and p.Arg408Trp (PMID: 23357515). Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3.

#	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 Baylor Genetics, SCV004209663.1

#	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

Last Updated: Sep 29, 2024

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