PAH-specific ACMG/AMP criteria applied: PP4: Phe>120 umol/L with PKU (PMID:25456745); PM3: In trans with: c.842+2T>A (P, ClinGen) (PMID:25456745); PS3: 0% in BioPKU; PM2: Extremely low frequency. ExAC MAF=0.00012; PM4: In frame deletion. 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: (PP4, PM3, PS3, PM2, PM4).
ClinVar Genomic variation as it relates to human health
NM_000277.3(PAH):c.208_210del (p.Ser70del)
Germline
Top reviewed classifications are shown here.
Submission summary:
Reviewed by expert panel
Pathogenic
for
Phenylketonuria
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000277.3(PAH):c.208_210del (p.Ser70del)
Variation ID: 102632 Accession: VCV000102632.14
- Type and length
-
Deletion, 3 bp
- Location
-
Cytogenetic: 12q23.2 12: 102894877-102894879 (GRCh38) [ NCBI UCSC ] 12: 103288655-103288657 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Mar 19, 2014 Jun 17, 2024 Aug 5, 2018 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000277.3:c.208_210del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000268.1:p.Ser70del inframe deletion NM_000277.3:c.208_210delTCT MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000277.1:c.206_208delCTT NM_000277.1:c.207_209delTTC NM_000277.1:c.208_210del NM_001354304.2:c.208_210del NP_001341233.1:p.Ser70del inframe deletion NC_000012.12:g.102894879_102894881del NC_000012.11:g.103288657_103288659del NG_008690.2:g.68532_68534del - Protein change
- S70del
- Other names
-
NM_000277.1(PAH):c.208_210delTCT
- Canonical SPDI
- NC_000012.12:102894876:AGAAG:AG
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| PAH | - | - |
GRCh38 GRCh37 |
1508 | 1631 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| not provided (3) |
no classification provided
|
- | RCV000088875.4 | |
| Pathogenic (7) |
reviewed by expert panel
|
Aug 5, 2018 | RCV000411181.17 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Aug 05, 2018)
|
reviewed by expert panel
Method: curation
|
Phenylketonuria
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
ClinGen PAH Variant Curation Expert Panel
FDA Recognized Database
Accession: SCV000852172.4 First in ClinVar: Dec 26, 2017 Last updated: Dec 11, 2022 |
Comment:
PAH-specific ACMG/AMP criteria applied: PP4: Phe>120 umol/L with PKU (PMID:25456745); PM3: In trans with: c.842+2T>A (P, ClinGen) (PMID:25456745); PS3: 0% in BioPKU; PM2: Extremely low … (more)
PAH-specific ACMG/AMP criteria applied: PP4: Phe>120 umol/L with PKU (PMID:25456745); PM3: In trans with: c.842+2T>A (P, ClinGen) (PMID:25456745); PS3: 0% in BioPKU; PM2: Extremely low frequency. ExAC MAF=0.00012; PM4: In frame deletion. 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: (PP4, PM3, PS3, PM2, PM4). (less)
|
|
|
Pathogenic
(Jan 11, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000629188.5
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This variant, c.208_210del, results in the deletion of 1 amino acid(s) of the PAH protein (p.Ser70del), but otherwise preserves the integrity of the reading frame. … (more)
This variant, c.208_210del, results in the deletion of 1 amino acid(s) of the PAH protein (p.Ser70del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs62642094, gnomAD 0.006%). This variant has been observed in individual(s) with PAH-related diseases from mild hyperphenylalaninemia to classic phenylketonuria (PMID: 15503242, 16256386, 23271928, 23932990; Invitae). ClinVar contains an entry for this variant (Variation ID: 102632). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Nov 24, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000485378.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
|
|
|
Pathogenic
(Jul 26, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002016477.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Nov 17, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004209585.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Oct 07, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002015201.1
First in ClinVar: Nov 20, 2021 Last updated: Nov 20, 2021 |
Comment:
Variant summary: PAH c.208_210delTCT (p.Ser70del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein that is located … (more)
Variant summary: PAH c.208_210delTCT (p.Ser70del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein that is located in the ACT domain (IPR002912), which proposed to have a regulatory role in protein function (InterPro). The variant allele was found at a frequency of 1.2e-05 in 251342 control chromosomes (gnomAD). c.208_210delTCT has been reported in the literature in several compound heterozygous and homozygous individuals (mostly of East Asian origin) who were affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria), with reported disease phenotypes ranging from mild hyperphenylalaninemia to classic phenylketonuria (e.g. Okano_1998, Okano_2011, Zhu_2013, Tao_2015, Li_2018, Su_2019, Tao_2021); of note, in the 5 reported homozygous patients a mild PKU phenotype was described (Li_2018, Su_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four submitters, including an expert panel (ClinGen PAH Variant Curation Expert Panel), have provided clinical-significance assessments for this variant in ClinVar after 2014, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001455114.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
|
not provided
(-)
|
no classification provided
Method: not provided
|
not provided
Affected status: not provided
Allele origin:
not provided
|
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE
Accession: SCV000119472.1
First in ClinVar: Mar 19, 2014 Last updated: Mar 19, 2014 |
|
|
|
not provided
(-)
|
Flagged submission
flagged submission
Method: not provided
Reason: This record appears to be redundant with a more recent record from the same submitter.
Notes: SCV000119469 appears to be redundant with SCV000119472.
(less)
Notes: SCV000119469 appears to
(...more)
Source: NCBI
|
not provided
Affected status: not provided
Allele origin:
not provided
|
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE
Accession: SCV000119469.1
First in ClinVar: Mar 19, 2014 Last updated: Mar 19, 2014 |
|
|
|
not provided
(-)
|
Flagged submission
flagged submission
Method: not provided
Reason: This record appears to be redundant with a more recent record from the same submitter.
Notes: SCV000119470 appears to be redundant with SCV000119472.
(less)
Notes: SCV000119470 appears to
(...more)
Source: NCBI
|
not provided
Affected status: not provided
Allele origin:
not provided
|
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE
Accession: SCV000119470.1
First in ClinVar: Mar 19, 2014 Last updated: Mar 19, 2014 |
|
|
| Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more | |||||
Comment:
Comment:
This variant, c.208_210del, results in the deletion of 1 amino acid(s) of the PAH protein (p.Ser70del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs62642094, gnomAD 0.006%). This variant has been observed in individual(s) with PAH-related diseases from mild hyperphenylalaninemia to classic phenylketonuria (PMID: 15503242, 16256386, 23271928, 23932990; Invitae). ClinVar contains an entry for this variant (Variation ID: 102632). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant summary: PAH c.208_210delTCT (p.Ser70del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein that is located in the ACT domain (IPR002912), which proposed to have a regulatory role in protein function (InterPro). The variant allele was found at a frequency of 1.2e-05 in 251342 control chromosomes (gnomAD). c.208_210delTCT has been reported in the literature in several compound heterozygous and homozygous individuals (mostly of East Asian origin) who were affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria), with reported disease phenotypes ranging from mild hyperphenylalaninemia to classic phenylketonuria (e.g. Okano_1998, Okano_2011, Zhu_2013, Tao_2015, Li_2018, Su_2019, Tao_2021); of note, in the 5 reported homozygous patients a mild PKU phenotype was described (Li_2018, Su_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four submitters, including an expert panel (ClinGen PAH Variant Curation Expert Panel), have provided clinical-significance assessments for this variant in ClinVar after 2014, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
PAH-specific ACMG/AMP criteria applied: PP4: Phe>120 umol/L with PKU (PMID:25456745); PM3: In trans with: c.842+2T>A (P, ClinGen) (PMID:25456745); PS3: 0% in BioPKU; PM2: Extremely low frequency. ExAC MAF=0.00012; PM4: In frame deletion. 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: (PP4, PM3, PS3, PM2, PM4).
Comment:
This variant, c.208_210del, results in the deletion of 1 amino acid(s) of the PAH protein (p.Ser70del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs62642094, gnomAD 0.006%). This variant has been observed in individual(s) with PAH-related diseases from mild hyperphenylalaninemia to classic phenylketonuria (PMID: 15503242, 16256386, 23271928, 23932990; Invitae). ClinVar contains an entry for this variant (Variation ID: 102632). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant summary: PAH c.208_210delTCT (p.Ser70del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein that is located in the ACT domain (IPR002912), which proposed to have a regulatory role in protein function (InterPro). The variant allele was found at a frequency of 1.2e-05 in 251342 control chromosomes (gnomAD). c.208_210delTCT has been reported in the literature in several compound heterozygous and homozygous individuals (mostly of East Asian origin) who were affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria), with reported disease phenotypes ranging from mild hyperphenylalaninemia to classic phenylketonuria (e.g. Okano_1998, Okano_2011, Zhu_2013, Tao_2015, Li_2018, Su_2019, Tao_2021); of note, in the 5 reported homozygous patients a mild PKU phenotype was described (Li_2018, Su_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four submitters, including an expert panel (ClinGen PAH Variant Curation Expert Panel), have provided clinical-significance assessments for this variant in ClinVar after 2014, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Spectrum of PAH gene mutations and genotype-phenotype correlation in patients with phenylalanine hydroxylase deficiency from Shanxi province. | Tao Y | Brain & development | 2021 | PMID: 32893076 |
| The Genetic Landscape and Epidemiology of Phenylketonuria. | Hillert A | American journal of human genetics | 2020 | PMID: 32668217 |
| The molecular epidemiology of hyperphenylalaninemia in Uygur population: incidence from newborn screening and mutational spectra. | Su Y | Annals of translational medicine | 2019 | PMID: 31355225 |
| Pilot study of expanded carrier screening for 11 recessive diseases in China: results from 10,476 ethnically diverse couples. | Zhao S | European journal of human genetics : EJHG | 2019 | PMID: 30275481 |
| Correlation between genotype and the tetrahydrobiopterin-responsive phenotype in Chinese patients with phenylketonuria. | Tao J | Pediatric research | 2015 | PMID: 26322415 |
| Fast clinical molecular diagnosis of hyperphenylalaninemia using next-generation sequencing-based on a custom AmpliSeq™ panel and Ion Torrent PGM sequencing. | Cao YY | Molecular genetics and metabolism | 2014 | PMID: 25456745 |
| The mutation spectrum of the phenylalanine hydroxylase (PAH) gene and associated haplotypes reveal ethnic heterogeneity in the Taiwanese population. | Liang Y | Journal of human genetics | 2014 | PMID: 24401910 |
| Variations in genotype-phenotype correlations in phenylalanine hydroxylase deficiency in Chinese Han population. | Zhu T | Gene | 2013 | PMID: 23932990 |
| Mutations of the phenylalanine hydroxylase gene in patients with phenylketonuria in Shanxi, China. | Zhou YA | Genetics and molecular biology | 2012 | PMID: 23271928 |
| Molecular characterization of phenylketonuria and tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency in Japan. | Okano Y | Journal of human genetics | 2011 | PMID: 21307867 |
| Phenylketonuria mutations in Northern China. | Song F | Molecular genetics and metabolism | 2005 | PMID: 16256386 |
| The molecular basis of phenylketonuria in Koreans. | Lee DH | Journal of human genetics | 2004 | PMID: 15503242 |
| Molecular characterization of phenylketonuria in Japanese patients. | Okano Y | Human genetics | 1998 | PMID: 9860305 |
| https://erepo.clinicalgenome.org/evrepo/ui/interpretation/ea84cf1d-348b-4e04-a809-550ce2b8d111 | - | - | - | - |
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Text-mined citations for rs62642094 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.