NM_000277.3(PAH):c.665A>G (p.Asp222Gly) AND Phenylketonuria

Germline classification:: Likely pathogenic (5 submissions)
Last evaluated:: Jul 9, 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:: RCV001381395.10

Allele description [Variation Report for NM_000277.3(PAH):c.665A>G (p.Asp222Gly)]

NM_000277.3(PAH):c.665A>G (p.Asp222Gly)

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.665A>G (p.Asp222Gly)

Other names:

NM_000277.1(PAH):c.665A>G; p.Asp222Gly

HGVS:

NC_000012.12:g.102855177T>C
NG_008690.2:g.108234A>G
NM_000277.3:c.665A>GMANE SELECT
NM_001354304.2:c.665A>G
NP_000268.1:p.Asp222Gly
NP_001341233.1:p.Asp222Gly
NC_000012.11:g.103248955T>C
NM_000277.1:c.665A>G

Protein change:

D222G

Links:

dbSNP: rs62507319

NCBI 1000 Genomes Browser:

rs62507319

Molecular consequence:

NM_000277.3:c.665A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354304.2:c.665A>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
SCV001579773	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 27, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 9429153, 10598814, 32668217, 28492532
SCV002032209	ClinGen PAH Variant Curation Expert Panel	reviewed by expert panel (ClinGen PAH ACMG Specifications v1)	Likely pathogenic (Jul 9, 2020)	germline	curation	PubMed (6) [See all records that cite these PMIDs] 24510552, 12409276, 23842451, 9429153, 15589814, 25757997 Citation Link,
SCV002511463	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Apr 26, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 17935162, 30747360, 9429153 Citation Link,
SCV003810754	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 23, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004209708	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 23, 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

Mutational spectrum of phenylalanine hydroxylase deficiency in the population resident in Catalonia: genotype-phenotype correlation.

Mallolas J, Vilaseca MA, Campistol J, Lambruschini N, Cambra FJ, Estivill X, Milà M.

Hum Genet. 1999 Nov;105(5):468-73.

PubMed [citation]

PMID:: 10598814

The Genetic Landscape and Epidemiology of Phenylketonuria.

Hillert A, Anikster Y, Belanger-Quintana A, Burlina A, Burton BK, Carducci C, Chiesa AE, Christodoulou J, Đorđević M, Desviat LR, Eliyahu A, Evers RAF, Fajkusova L, Feillet F, Bonfim-Freitas PE, Giżewska M, Gundorova P, Karall D, Kneller K, Kutsev SI, Leuzzi V, Levy HL, et al.

Am J Hum Genet. 2020 Aug 6;107(2):234-250. doi: 10.1016/j.ajhg.2020.06.006. Epub 2020 Jul 14.

PubMed [citation]

PMID:: 32668217
PMCID:: PMC7413859

See all PubMed Citations (12)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001579773.4

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

Description

For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 102775). This missense change has been observed in individual(s) with phenylketonuria (PMID: 9429153, 10598814, 32668217). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 222 of the PAH protein (p.Asp222Gly).

#	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, SCV002032209.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (6)

Description

The c.665A>G (p.Asp222Gly) variant in PAH has been reported in multiple individuals with PAH deficiency (PMID: 24510552, 9429153); One had BH4 cofactor deficiency excluded (PMID: 15589814). This variant is absent in population databases. This variant was detected with multiple pathogenic variants: p.A104D (PMID: 9429153); p.R408W (PMID: 15589814); c.1066-11G>A (PMID: 23842451); p.L48S (PMID: 25757997); p.I65T (PMID: 16165389). 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_strong.

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002511463.1

#	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.665A>G (p.Asp222Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251340 control chromosomes. c.665A>G has been reported in the literature in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria). These data indicate that the variant is likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic/likely pathogenic. 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

From Revvity Omics, Revvity, SCV003810754.2

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004209708.1

#	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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