ClinVar Genomic variation as it relates to human health
NM_006623.4(PHGDH):c.357-1G>A
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_006623.4(PHGDH):c.357-1G>A
Variation ID: 1098314 Accession: VCV001098314.6
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 1p12 1: 119726850 (GRCh38) [ NCBI UCSC ] 1: 120269473 (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 May 20, 2021 Feb 20, 2024 Sep 29, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_006623.4:c.357-1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice acceptor NC_000001.11:g.119726850G>A NC_000001.10:g.120269473G>A NG_009188.1:g.20055G>A - Protein change
- Other names
- -
- Canonical SPDI
- NC_000001.11:119726849:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- effect on RNA splicing Variation Ontology [VariO:0362]
- Decreased function
-
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.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD), exomes 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
- 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. |
|||
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 (3) |
criteria provided, multiple submitters, no conflicts
|
Apr 11, 2023 | RCV001420191.4 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Sep 29, 2023 | RCV002554083.3 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
Mar 28, 2022 | RCV003128765.1 |
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
(Dec 07, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Neu-Laxova syndrome 1
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV001622388.1
First in ClinVar: May 20, 2021 Last updated: May 20, 2021 |
Comment:
A heterozygous 3’splice site variation in intron 3 of the PHGDH gene that affects the invariant AG acceptor splice site upstream of exon 4 was … (more)
A heterozygous 3’splice site variation in intron 3 of the PHGDH gene that affects the invariant AG acceptor splice site upstream of exon 4 was detected. The observed variant c.3357-1G>A has not been reported in the 1000 genomes and has a minor allele frequency of 0.008% in the gnomAD databases. The in silico prediction of the variant is damaging by MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic. (less)
Clinical Features:
Lissencephaly (present) , Ventriculomegaly (present) , Corpus callosum, agenesis of (present) , Cerebral hypoplasia (present) , Lumbar kyphosis (present)
Age: 30-39 years
Sex: female
Ethnicity/Population group: Hindu
Geographic origin: India
Method: DNA was used to perform targeted gene capture using a custom capture kit. Libraries were sequenced to mean >80-100X coverage on the Illumina sequencing platform. Sequence obtained were aligned to human references genome using BWA program and analyzed using Picard and GATK-Lite toolkit to identify variants in the targeted genes relevant to clinical indication.
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: research
|
Neu-Laxova syndrome 1
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Diagnostics Division, CENTRE FOR DNA FINGERPRINTING AND DIAGNOSTICS
Accession: SCV002549053.1
First in ClinVar: Jul 28, 2022 Last updated: Jul 28, 2022 |
|
|
Likely pathogenic
(Mar 28, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV003805634.1
First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023 |
Comment:
Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Not observed … (more)
Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge (less)
|
|
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: SCV004049058.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
|
|
Likely pathogenic
(Apr 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
PHGDH deficiency
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV004049059.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
|
|
Likely pathogenic
(Sep 29, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
PHGDH deficiency
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV003476866.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 2024 |
Comment:
This sequence change affects an acceptor splice site in intron 3 of the PHGDH gene. It is expected to disrupt RNA splicing. Variants that disrupt … (more)
This sequence change affects an acceptor splice site in intron 3 of the PHGDH gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PHGDH are known to be pathogenic (PMID: 14645240, 24836451). This variant is present in population databases (rs766427173, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with PHGDH-related conditions. ClinVar contains an entry for this variant (Variation ID: 1098314). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
|
Germline Functional Evidence
Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
---|---|---|---|---|
effect on RNA splicing
|
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV001622388.1
|
|
||
Decreased function
|
|
|
Diagnostics Division, CENTRE FOR DNA FINGERPRINTING AND DIAGNOSTICS
Accession: SCV002549053.1
|
|
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
Neu-Laxova syndrome, an inborn error of serine metabolism, is caused by mutations in PHGDH. | Shaheen R | American journal of human genetics | 2014 | PMID: 24836451 |
Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
Targeted disruption of the mouse 3-phosphoglycerate dehydrogenase gene causes severe neurodevelopmental defects and results in embryonic lethality. | Yoshida K | The Journal of biological chemistry | 2004 | PMID: 14645240 |
Text-mined citations for rs766427173 ...
HelpRecord last updated Jun 23, 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.