NM_000277.3(PAH):c.1184C>G (p.Ala395Gly) AND Phenylketonuria

Germline classification:: Pathogenic/Likely pathogenic (8 submissions)
Last evaluated:: Feb 21, 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:: RCV000410586.19

Allele description [Variation Report for NM_000277.3(PAH):c.1184C>G (p.Ala395Gly)]

NM_000277.3(PAH):c.1184C>G (p.Ala395Gly)

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.1184C>G (p.Ala395Gly)

HGVS:

NC_000012.12:g.102843661G>C
NG_008690.2:g.119750C>G
NM_000277.3:c.1184C>GMANE SELECT
NM_001354304.2:c.1184C>G
NP_000268.1:p.Ala395Gly
NP_001341233.1:p.Ala395Gly
NC_000012.11:g.103237439G>C
NM_000277.1:c.1184C>G
P00439:p.Ala395Gly

Protein change:

A395G

Links:

UniProtKB: P00439#VAR_001030; dbSNP: rs62508736

NCBI 1000 Genomes Browser:

rs62508736

Molecular consequence:

NM_000277.3:c.1184C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354304.2:c.1184C>G - 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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000485283	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Jul 18, 2016)	unknown	clinical testing	mdi-5618_320494_Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015).pdf, Citation Link,
SCV000536786	Division of Human Genetics, Children's Hospital of Philadelphia - CSER-PediSeq	no assertion criteria provided	Likely pathogenic (Apr 28, 2016)	paternal	research	PubMed (1) [See all records that cite this PMID]
SCV000917929	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Nov 16, 2018)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 10429004, 18299955 Citation Link,
SCV001220571	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 3, 2023)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 18299955, 24368688, 27121329, 7726156, 11161839, 11999982, 17502162, 22841515, 28492532
SCV002088623	Natera, Inc.	no assertion criteria provided	Pathogenic (Feb 17, 2021)	germline	clinical testing
SCV002521635	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 22, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004209644	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 21, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004848853	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 3, 2022)	germline	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	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	paternal	unknown	not provided	not provided	not provided	not provided	not provided	research
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Phenylketonuria mutations in Northern China.

Song F, Qu YJ, Zhang T, Jin YW, Wang H, Zheng XY.

Mol Genet Metab. 2005 Dec;86 Suppl 1:S107-18. Epub 2005 Oct 26.

PubMed [citation]

PMID:: 16256386

Relationship among genotype, biochemical phenotype, and cognitive performance in females with phenylalanine hydroxylase deficiency: report from the Maternal Phenylketonuria Collaborative Study.

Güttler F, Azen C, Guldberg P, Romstad A, Hanley WB, Levy HL, Matalon R, Rouse BM, Trefz F, de la Cruz F, Koch R.

Pediatrics. 1999 Aug;104(2 Pt 1):258-62.

PubMed [citation]

PMID:: 10429004

See all PubMed Citations (12)

Details of each submission

From Counsyl, SCV000485283.2

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

From Division of Human Genetics, Children's Hospital of Philadelphia - CSER-PediSeq, SCV000536786.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	paternal	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, SCV000917929.1

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

Description

Variant summary: PAH c.1184C>G (p.Ala395Gly) results in a non-conservative amino acid change located in the C-terminal domain, containing the catalytic domain and the coiled-coil C-terminal oligomerization motif (IPR019774) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-06 in 276980 control chromosomes (gnomAD). c.1184C>G has been reported in the literature in a homozygous individual affected with mild Hyperphenylalaninemia (MHP) (Bercovich 2008) and multiple compound heterozugous individuals affected with MHP or mild to moderate PKU phenotype (Guttler 1999, Bercovich 2008, Aldamiz-Echevarria 2016). These data indicate that the variant is very likely to be associated with disease; however, in general, patients with mild hyperphenylalaninemia do not require restrictive diet or supplementary treatment unless Phe concentrations reach the clinical threshold. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as 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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001220571.5

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

Description

This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 395 of the PAH protein (p.Ala395Gly). This variant is present in population databases (rs62508736, gnomAD 0.002%). This missense change has been observed in individual(s) with hyperphenylalaninemi and/or phenylketonuria (PMID: 18299955, 24368688, 27121329). ClinVar contains an entry for this variant (Variation ID: 102549). 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 expected to disrupt PAH protein function with a positive predictive value of 80%. This variant disrupts the p.Ala395 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7726156, 11161839, 11999982, 17502162, 22841515). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 Natera, Inc., SCV002088623.1

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

From 3billion, SCV002521635.1

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

Description

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.98; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000102549). A different missense change at the same codon (p.Ala395Pro) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000102547). 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

From Baylor Genetics, SCV004209644.2

#	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 Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004848853.1

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

Description

The p.Ala395Gly variant in PAH has been reported in at least 1 homozygous and > 15 compound heterozygous individuals affected with mild Hyperphenylalaninemia or mild to moderate Phenylketonuria (Guldberg 1998 PMID: 9634518, Guttler 1999 PMID: 10429004, Bercovich 2008 PMID: 18299955, Hillert 2020 PMID: 32668217). It has also been reported in ClinVar (Variation ID 102549) and was identified in 1/67986 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Another variant involving this codon (p.Ala395Pro) has been identified in individuals with Phenylketonuria and is classified as pathogenic by clinical laboratories in ClinVar. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hyperphenylalanemia/phenylkenonuria. ACMG/AMP Criteria applied: PM2_Supporting, PP3, PM3_Very strong, PM5.

#	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: Sep 29, 2024

Relating variation to medicine