NM_000277.3(PAH):c.1223G>A (p.Arg408Gln) AND Phenylketonuria
- Germline classification:
- Pathogenic (12 submissions)
- Last evaluated:
- Aug 5, 2018
- Review status:
- 3 stars out of maximum of 4 starsreviewed by expert panel
- Somatic classification
of clinical impact: - None
- Review status:
- (0/4) 0 stars out of maximum of 4 starsno assertion criteria provided
- Somatic classification
of oncogenicity: - None
- Review status:
- (0/4) 0 stars out of maximum of 4 starsno assertion criteria provided
- Record status:
- current
- Accession:
- RCV000000643.95
Allele description [Variation Report for NM_000277.3(PAH):c.1223G>A (p.Arg408Gln)]
NM_000277.3(PAH):c.1223G>A (p.Arg408Gln)
- 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.1223G>A (p.Arg408Gln)
- Other names:
- NM_000277.1(PAH):c.1223G>A
- HGVS:
- NC_000012.12:g.102840492C>T
- NG_008690.2:g.122919G>A
- NM_000277.3:c.1223G>AMANE SELECT
- NM_001354304.2:c.1223G>A
- NP_000268.1:p.Arg408Gln
- NP_001341233.1:p.Arg408Gln
- NC_000012.11:g.103234270C>T
- NM_000277.1:c.1223G>A
- NM_000277.2:c.1223G>A
- P00439:p.Arg408Gln
- c.1223G>A (p.Arg408Gln)
This HGVS expression did not pass validation- Protein change:
- R408Q; ARG408GLN
- Links:
- UniProtKB: P00439#VAR_001034; OMIM: 612349.0038; dbSNP: rs5030859
- NCBI 1000 Genomes Browser:
- rs5030859
- Molecular consequence:
- NM_000277.3:c.1223G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001354304.2:c.1223G>A - missense variant - [Sequence Ontology: SO:0001583]
- Observations:
- 1
Condition(s)
Assertion and evidence details
Submission Accession | Submitter | Review Status (Assertion method) | Clinical Significance (Last evaluated) | Origin | Method | Citations |
---|---|---|---|---|---|---|
SCV000020793 | OMIM | no assertion criteria provided | Pathogenic (Aug 1, 1992) | germline | literature only | |
SCV000830376 | Invitae | criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) | Pathogenic (Jan 20, 2024) | germline | clinical testing | |
SCV000852159 | ClinGen PAH Variant Curation Expert Panel | reviewed by expert panel (ClinGen PAH ACMG Specifications v1) | Pathogenic (Aug 5, 2018) | germline | curation | |
SCV000919913 | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) | Pathogenic (Jan 8, 2018) | germline | clinical testing | |
SCV001163710 | Baylor Genetics | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Mar 26, 2024) | unknown | clinical testing | |
SCV001194182 | Myriad Genetics, Inc. | criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019)) | Pathogenic (Dec 19, 2019) | unknown | clinical testing | |
SCV001458998 | Natera, Inc. | no assertion criteria provided | Pathogenic (Sep 16, 2020) | germline | clinical testing | |
SCV002016494 | Revvity Omics, Revvity | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Jul 26, 2021) | germline | clinical testing | |
SCV002768000 | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
| criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (May 6, 2021) | germline | clinical testing | |
SCV002810394 | Fulgent Genetics, Fulgent Genetics | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Dec 15, 2021) | unknown | clinical testing | |
SCV004035236 | Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences | criteria provided, single submitter (Zastrow et al. (Hum Mutat. 2018)) | Pathogenic Score: 30311390 (Sep 19, 2023) | inherited | clinical testing | |
SCV004800860 | Neonatal Disease Screening Center, Medical Genetics Center, Huaihua City Maternal and Child Health Care Hospital | no assertion criteria provided (ACMG Guidelines, 2015) | Pathogenic | germline | clinical testing |
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 |
not provided | germline | not provided | not provided | not provided | not provided | not provided | not provided | literature only |
Dong | germline | yes | 1 | not provided | not provided | 1 | not provided | clinical testing |
turkish | inherited | yes | not provided | not provided | not provided | not provided | not provided | clinical testing |
Citations
PubMed
Ellingsen S, Knappskog PM, Apold J, Eiken HG.
FEBS Lett. 1999 Sep 3;457(3):505-8.
- PMID:
- 10471838
Ye J, Chen C, Yuan Y, Han L, Wang Y, Qiu W, Zhang H, Asan, Gu X.
Sci Rep. 2018 Jan 9;8(1):161. doi: 10.1038/s41598-017-18358-y.
- PMID:
- 29317692
- PMCID:
- PMC5760544
PMC
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Details of each submission
From OMIM, SCV000020793.66
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | literature only | PubMed (2) |
Description
In a Norwegian patient with phenylketonuria (PKU; 261600), Eiken et al. (1992) identified a novel mutation in exon 12 in association with haplotype 12 alleles, by use of SSCP analyses. A patient who was homozygous for the arg408-to-gln (R408Q) mutation exhibited a mild PKU variant. Eiken et al. (1992) mapped the district of origin of the R408Q and phe299-to-cys (F299C; 612349.0039) mutations by determining the birthplaces of the relevant grandparents. In contrast to both the overall distribution of PKU mutations and the general population density in Norway, the ancestors of these 2 mutations appeared to be restricted to the western and northern coastal districts. See 612349.0042.
In Chinese, Lin et al. (1992) found a G-to-A transition in codon 408 as the basis of phenylketonuria. The missense mutation resulted in the substitution of arginine for glutamine and accounted for about 5% of PKU chromosomes among Chinese. The mutation was in linkage disequilibrium with RFLP haplotype 4. The arg408-to-trp mutation (R408W; 612349.0002) is in the same codon.
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | not provided | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
From Invitae, SCV000830376.7
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (8) |
Description
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 408 of the PAH protein (p.Arg408Gln). This variant is present in population databases (rs5030859, gnomAD 0.03%). This missense change has been observed in individual(s) with PAH-related disease (PMID: 1312992, 10471838, 24401910, 29317692). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 612). 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%. Experimental studies have shown that this missense change affects PAH function (PMID: 12655546). This variant disrupts the p.Arg408 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 2014036, 12173030, 24401910). 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 ClinGen PAH Variant Curation Expert Panel, SCV000852159.4
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | curation | PubMed (3) |
Description
PAH-specific ACMG/AMP criteria applied: PM3_Strong: In trans with R408W, IVS4-1G>A, R241C (ClinGen, P) (PMID:1312992; PMID:14722928); PP3: ; PS3: Mutant enzyme activity of 46% in BioPKU (PMID:9860305); PP4_Moderate: ~830 uml/L w/o BH4 deficiency & 823 umol/L, BH4 status unknown (PMID:9860305; PMID:1312992). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM3_Strong, PP3, PS3, PP4_Moderate).
# | 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, SCV000919913.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (2) |
Description
Variant summary: The PAH c.1223G>A (p.Arg408Gln) variant located in the Aromatic amino acid hydroxylas, C-terminal domain (InterPro) involves the alteration of a conserved nucleotide and 4/5 in silico tools predict a damaging outcome for this variant. This variant was found in 13/277144 control chromosomes (gnomAD) at a frequency of 0.0000469, which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.0079057). Multiple publications have cited the variant in affected compound heterozygous individuals, presenting with a significant decrease in PAH activity. In support of this, there are other variants at the 408 codon that have been reported in patients with PKU (R408L, R408W), suggesting the codon is important for function. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is 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 Baylor Genetics, SCV001163710.2
# | 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 Myriad Genetics, Inc., SCV001194182.2
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (5) |
Description
NM_000277.1(PAH):c.1223G>A(R408Q) is classified as pathogenic in the context of phenylalanine hydroxylase deficiency and can be associated with variant or non-PKU HPA. Sources cited for classification include the following: PMID 14722928, 1312992, 1355066, 1301200, and 8533759. Classification of NM_000277.1(PAH):c.1223G>A(R408Q) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
# | 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 Natera, Inc., SCV001458998.1
# | 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 Revvity Omics, Revvity, SCV002016494.3
# | 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 Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002768000.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (3) |
Description
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with phenylketonuria (PKU; MIM#261600). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 14 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (252 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated catalytic domain (PMID: 30037505). (I) 0705 - The well-reported pathogenic variant, p.(Arg408Trp), affecting the same residue has previously been reported in association with phenylketonuria (ClinVar), however it is not considered a comparable variant as it has a major Grantham score, whereas this variant has a minor score, therefore cannot be used to inform pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple individuals with mild PKU, mild hyperphenylalaninemia ( MHP) and non-PKU hyperphenylalaninemia (ClinVar, PMID: 1312992). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Site-directed mutagenesis studies have shown a reduction of 41% in PAH activity compared to wild-type (PMID: 30037505). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
# | 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 Fulgent Genetics, Fulgent Genetics, SCV002810394.1
# | 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 |
From Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences, SCV004035236.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | turkish | not provided | not provided | not provided | clinical testing | PubMed (2) |
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | inherited | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
From Neonatal Disease Screening Center, Medical Genetics Center, Huaihua City Maternal and Child Health Care Hospital, SCV004800860.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | Dong | 1 | not provided | not provided | clinical testing | not provided |
Description
PS3+PM3_VS+PM5+PP1+PP3+PP4_M
# | 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: Jul 7, 2024