NM_000277.3(PAH):c.676C>A (p.Gln226Lys) AND Phenylketonuria

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Mar 14, 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:: RCV001199975.2

Allele description [Variation Report for NM_000277.3(PAH):c.676C>A (p.Gln226Lys)]

NM_000277.3(PAH):c.676C>A (p.Gln226Lys)

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.676C>A (p.Gln226Lys)

HGVS:

NC_000012.12:g.102855166G>T
NG_008690.2:g.108245C>A
NM_000277.3:c.676C>AMANE SELECT
NM_001354304.2:c.676C>A
NP_000268.1:p.Gln226Lys
NP_001341233.1:p.Gln226Lys
NC_000012.11:g.103248944G>T
NM_000277.1:c.676C>A

Protein change:

Q226K

Links:

dbSNP: rs62508696

NCBI 1000 Genomes Browser:

rs62508696

Molecular consequence:

NM_000277.3:c.676C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354304.2:c.676C>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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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SARM1 sterile alpha and TIR motif containing 1 [Homo sapiens]
SARM1 sterile alpha and TIR motif containing 1 [Homo sapiens]
Gene ID:23098

Gene
23098[uid] AND (alive[prop]) (1)
Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001370797	ClinGen PAH Variant Curation Expert Panel	reviewed by expert panel (ClinGen PAH ACMG Specifications v1)	Likely pathogenic (Mar 14, 2020)	germline	curation	PubMed (2) [See all records that cite these PMIDs] 29654578, 26481238 Citation Link,
SCV002058443	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 3, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] PMID:26481238

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001370797

ClinGen PAH Variant Curation Expert Panel

reviewed by expert panel

(ClinGen PAH ACMG Specifications v1)

Likely pathogenic
(Mar 14, 2020)

germline

curation

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

Citation Link,

SCV002058443

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 3, 2022)

germline

clinical testing

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

PMID:26481238

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	curation
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

Functional Characterization of Novel Phenylalanine Hydroxylase p.Gln226Lys Mutation Revealed Its Non-responsiveness to Tetrahydrobiopterin Treatment in Hepatoma Cellular Model.

Klaassen K, Djordjevic M, Skakic A, Desviat LR, Pavlovic S, Perez B, Stojiljkovic M.

Biochem Genet. 2018 Oct;56(5):533-541. doi: 10.1007/s10528-018-9858-5. Epub 2018 Apr 13.

PubMed [citation]

PMID:: 29654578

A novel common large genomic deletion and two new missense mutations identified in the Romanian phenylketonuria population.

Gemperle-Britschgi C, Iorgulescu D, Mager MA, Anton-Paduraru D, Vulturar R, Thöny B.

Gene. 2016 Jan 15;576(1 Pt 1):182-8. doi: 10.1016/j.gene.2015.10.020. Epub 2015 Oct 21.

PubMed [citation]

PMID:: 26481238

See all PubMed Citations (3)

Details of each submission

From ClinGen PAH Variant Curation Expert Panel, SCV001370797.1

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

Description

The c.676C>A (p.Gln226Lys) variant in PAH has been reported in multiple individuals with PKU (BH4 deficiency excluded). (PMID 26481238, 29654578). This variant is absent in population databases. This variant was detected in trans with pathogenic variants p.Gln20* and p.Ile306Val. Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong, PP3.

#	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 3billion, SCV002058443.1

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

Description

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000932251, PMID:26481238, PS1_S). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals(PMID: 26481238, 29654578, PM3_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 29654578, PS3_S). A different missense change at the same codon has been reported to be associated with PAH related disorder (PMID:11678552, PM5_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.868, 3CNET: 0.989, PP3_P). A missense variant is a common mechanism associated with Phenylketonuria; PKU (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

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

Last Updated: Mar 18, 2023

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