Variant summary: The PHGDH c.1468G>A (p.Val490Met) variant involves the alteration of a conserved nucleotide. 2/3 in silico tools predict a benign outcome for this variant (SNPsandGO and MutationTaster not captured due to low reliability index). This variant was found in 13/123042 control chromosomes at a frequency of 0.0001059, which does not exceed the estimated maximal expected allele frequency of a pathogenic PHGDH variant (0.0026352). The variant has been reported in the homozygous state in numerousffected individuals, and functional studies showed the variant to result in significantly reduced enzyme activity in transfected cells as well as patient fibroblasts (Klomp_2000, Pind_2002). In addition, one reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_006623.4(PHGDH):c.1468G>A (p.Val490Met)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(10)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
10
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_006623.4(PHGDH):c.1468G>A (p.Val490Met)
Variation ID: 3867 Accession: VCV000003867.15
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 1p12 1: 119743906 (GRCh38) [ NCBI UCSC ] 1: 120286529 (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 7, 2015 Feb 14, 2024 Jan 16, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_006623.4:c.1468G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_006614.2:p.Val490Met missense NC_000001.11:g.119743906G>A NC_000001.10:g.120286529G>A NG_009188.1:g.37111G>A O43175:p.Val490Met - Protein change
- V490M
- Other names
- -
- Canonical SPDI
- NC_000001.11:119743905:G:A
-
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.
The Genome Aggregation Database (gnomAD) 0.00006
Trans-Omics for Precision Medicine (TOPMed) 0.00009
Exome Aggregation Consortium (ExAC) 0.00010
The Genome Aggregation Database (gnomAD), exomes 0.00015
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. |
|||
| PHGDH | - | - |
GRCh38 GRCh37 |
825 | 848 | |
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. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (7) |
criteria provided, multiple submitters, no conflicts
|
Jan 16, 2024 | RCV000004071.13 | |
|
See cases
|
Likely pathogenic (1) |
criteria provided, single submitter
|
Oct 2, 2019 | RCV002251869.2 |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Apr 11, 2023 | RCV003338378.1 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 19, 2022 | RCV002482824.1 |
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
(Jul 23, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
PHGDH deficiency
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000698713.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
Comment:
Variant summary: The PHGDH c.1468G>A (p.Val490Met) variant involves the alteration of a conserved nucleotide. 2/3 in silico tools predict a benign outcome for this variant … (more)
Variant summary: The PHGDH c.1468G>A (p.Val490Met) variant involves the alteration of a conserved nucleotide. 2/3 in silico tools predict a benign outcome for this variant (SNPsandGO and MutationTaster not captured due to low reliability index). This variant was found in 13/123042 control chromosomes at a frequency of 0.0001059, which does not exceed the estimated maximal expected allele frequency of a pathogenic PHGDH variant (0.0026352). The variant has been reported in the homozygous state in numerousffected individuals, and functional studies showed the variant to result in significantly reduced enzyme activity in transfected cells as well as patient fibroblasts (Klomp_2000, Pind_2002). In addition, one reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
|
|
|
Pathogenic
(May 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
PHGDH deficiency
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001135397.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
|
|
|
Pathogenic
(Jun 05, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
PHOSPHOGLYCERATE DEHYDROGENASE DEFICIENCY
Affected status: yes
Allele origin:
germline
|
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV001984849.1
First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021 |
Comment:
This variant has been reported in several individuals affected with phosphoglycerate dehydrogenase deficiency and was found to segregate with the disease in related individuals (PMID: … (more)
This variant has been reported in several individuals affected with phosphoglycerate dehydrogenase deficiency and was found to segregate with the disease in related individuals (PMID: 11055895, 11751922). Functional studies have shown that this change disrupts PHGDH enzymatic activity in vitro (PMID: 11055895, 11751922). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.00014 (40/281324) and thus is presumed to be rare. In silico analyses are suggestive of deleterious effect of the c.1468G>A (p.Val490Met) variant on protein function. Based on the available evidence, the c.1468G>A (p.Val490Met) variant is classified as Pathogenic. (less)
|
|
|
Likely pathogenic
(Oct 02, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
See cases
Affected status: yes
Allele origin:
germline
|
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002523267.1
First in ClinVar: Jun 09, 2022 Last updated: Jun 09, 2022 |
Comment:
ACMG classification criteria: PS3, PS4, PP1, PP3
Clinical Features:
Aplasia/Hypoplasia of the corpus callosum (present) , Abnormal cerebellar vermis morphology (present) , Abnormal basal ganglia morphology (present) , Abnormal cerebellum morphology (present)
Geographic origin: Brazil
|
|
|
Pathogenic
(Mar 19, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Neu-Laxova syndrome 1
PHGDH deficiency
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002790572.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Likely pathogenic
(Apr 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
PHGDH deficiency
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV004049139.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
|
|
|
Likely pathogenic
(Apr 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Neu-Laxova syndrome 1
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV004049138.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
|
|
|
Pathogenic
(Jan 16, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
PHGDH deficiency
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000951673.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 490 of the PHGDH protein (p.Val490Met). … (more)
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 490 of the PHGDH protein (p.Val490Met). This variant is present in population databases (rs121907987, gnomAD 0.2%). This missense change has been observed in individuals with phosphoglycerate dehydrogenase deficiency (PMID: 11055895, 11751922). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3867). 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 PHGDH protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PHGDH function (PMID: 11055895, 11751922). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Dec 01, 2000)
|
no assertion criteria provided
Method: literature only
|
PHOSPHOGLYCERATE DEHYDROGENASE DEFICIENCY
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000024237.2
First in ClinVar: Apr 04, 2013 Last updated: Mar 07, 2015 |
Comment on evidence:
In 5 patients from 3 different families (2 Turkish and 1 European), Klomp et al. (2000) found that PHGDH deficiency (PHGDHD; 601815) was related to … (more)
In 5 patients from 3 different families (2 Turkish and 1 European), Klomp et al. (2000) found that PHGDH deficiency (PHGDHD; 601815) was related to a homozygous 1468G-A transition predicted to cause a val490-to-met amino acid substitution in the protein. (less)
|
|
|
Pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Phosphoglycerate dehydrogenase deficiency
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001461724.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
Comment:
Comment:
This variant has been reported in several individuals affected with phosphoglycerate dehydrogenase deficiency and was found to segregate with the disease in related individuals (PMID: 11055895, 11751922). Functional studies have shown that this change disrupts PHGDH enzymatic activity in vitro (PMID: 11055895, 11751922). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.00014 (40/281324) and thus is presumed to be rare. In silico analyses are suggestive of deleterious effect of the c.1468G>A (p.Val490Met) variant on protein function. Based on the available evidence, the c.1468G>A (p.Val490Met) variant is classified as Pathogenic.
Comment:
ACMG classification criteria: PS3, PS4, PP1, PP3
Comment:
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 490 of the PHGDH protein (p.Val490Met). This variant is present in population databases (rs121907987, gnomAD 0.2%). This missense change has been observed in individuals with phosphoglycerate dehydrogenase deficiency (PMID: 11055895, 11751922). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3867). 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 PHGDH protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PHGDH function (PMID: 11055895, 11751922). For these reasons, this variant has been 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:
Variant summary: The PHGDH c.1468G>A (p.Val490Met) variant involves the alteration of a conserved nucleotide. 2/3 in silico tools predict a benign outcome for this variant (SNPsandGO and MutationTaster not captured due to low reliability index). This variant was found in 13/123042 control chromosomes at a frequency of 0.0001059, which does not exceed the estimated maximal expected allele frequency of a pathogenic PHGDH variant (0.0026352). The variant has been reported in the homozygous state in numerousffected individuals, and functional studies showed the variant to result in significantly reduced enzyme activity in transfected cells as well as patient fibroblasts (Klomp_2000, Pind_2002). In addition, one reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Comment:
This variant has been reported in several individuals affected with phosphoglycerate dehydrogenase deficiency and was found to segregate with the disease in related individuals (PMID: 11055895, 11751922). Functional studies have shown that this change disrupts PHGDH enzymatic activity in vitro (PMID: 11055895, 11751922). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.00014 (40/281324) and thus is presumed to be rare. In silico analyses are suggestive of deleterious effect of the c.1468G>A (p.Val490Met) variant on protein function. Based on the available evidence, the c.1468G>A (p.Val490Met) variant is classified as Pathogenic.
Comment:
ACMG classification criteria: PS3, PS4, PP1, PP3
Comment:
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 490 of the PHGDH protein (p.Val490Met). This variant is present in population databases (rs121907987, gnomAD 0.2%). This missense change has been observed in individuals with phosphoglycerate dehydrogenase deficiency (PMID: 11055895, 11751922). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3867). 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 PHGDH protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PHGDH function (PMID: 11055895, 11751922). For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Molecular characterization of 3-phosphoglycerate dehydrogenase deficiency--a neurometabolic disorder associated with reduced L-serine biosynthesis. | Klomp LW | American journal of human genetics | 2000 | PMID: 11055895 |
Text-mined citations for rs121907987 ...
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 Feb 20, 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.