Based on the classification scheme VCGS_Germline_v1.3.3, 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 Neu-Laxova syndrome 2 (MIM#616038). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to valine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD v2 <0.01 for a recessive condition (43 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated aminotransferase class-V domain (PDB). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic and likely pathogenic, in multiple homozygous and compound heterozygous patients with Neu-Laxova syndrome. As a common polymorphism is sometimes found in cis with this variant, it has also been reported as c.296_297delinsTG (ClinVar, PMID: 25152457, PMID: 26960553; PMID: 30293248). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Yeast growth assays demonstrate that this variant significantly impairs growth compared to wildtype (PMID: 32077105). (SP) 1206 - This variant has been shown to be paternally inherited (VCGS #20G001772). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
ClinVar Genomic variation as it relates to human health
NM_058179.4(PSAT1):c.296C>T (p.Ala99Val)
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.
(5)
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
5
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_058179.4(PSAT1):c.296C>T (p.Ala99Val)
Variation ID: 156364 Accession: VCV000156364.10
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9q21.2 9: 78304839 (GRCh38) [ NCBI UCSC ] 9: 80919755 (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 Aug 2, 2015 Feb 4, 2024 Jul 18, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_058179.4:c.296C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_478059.1:p.Ala99Val missense NM_021154.5:c.296C>T NP_066977.1:p.Ala99Val missense NM_058179.2:c.296C>T NM_058179.3:c.296C>T NC_000009.12:g.78304839C>T NC_000009.11:g.80919755C>T NG_012165.1:g.12697C>T Q9Y617:p.Ala99Val - Protein change
- A99V
- Other names
- -
- Canonical SPDI
- NC_000009.12:78304838:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
mutation affecting polypeptide function; Sequence Ontology [ SO:1000117]More impaired than known disease allele D100A. PMID:32077105 Table S7. [submitted by Dudley Research Group, Pacific Northwest Research Institute]loss_of_function_variant; Sequence Ontology [ SO:0002054]Equally or more impaired than known disease allele D100A. PMID:32077105 Table S7. [submitted by Dudley Research Group, Pacific Northwest Research Institute]
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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.
-
Exome Aggregation Consortium (ExAC) 0.00008
The Genome Aggregation Database (gnomAD), exomes 0.00016
The Genome Aggregation Database (gnomAD) 0.00019
Trans-Omics for Precision Medicine (TOPMed) 0.00019
- 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. |
|||
| PSAT1 | - | - |
GRCh38 GRCh37 |
487 | 528 | |
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 (2) |
criteria provided, single submitter
|
Oct 19, 2020 | RCV000144448.6 | |
| Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jul 18, 2023 | RCV001254372.7 |
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. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Jun 20, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV002064403.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
|
|
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Pathogenic
(Oct 19, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Neu-Laxova syndrome 2
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002768835.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.3, 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 Neu-Laxova syndrome 2 (MIM#616038). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to valine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD v2 <0.01 for a recessive condition (43 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated aminotransferase class-V domain (PDB). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic and likely pathogenic, in multiple homozygous and compound heterozygous patients with Neu-Laxova syndrome. As a common polymorphism is sometimes found in cis with this variant, it has also been reported as c.296_297delinsTG (ClinVar, PMID: 25152457, PMID: 26960553; PMID: 30293248). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Yeast growth assays demonstrate that this variant significantly impairs growth compared to wildtype (PMID: 32077105). (SP) 1206 - This variant has been shown to be paternally inherited (VCGS #20G001772). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
|
|
|
Likely pathogenic
(Jul 18, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV004238604.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Sep 04, 2014)
|
no assertion criteria provided
Method: literature only
|
NEU-LAXOVA SYNDROME 2
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000189515.3
First in ClinVar: Oct 06, 2014 Last updated: May 31, 2020 |
Comment on evidence:
In 2 affected stillborn fetuses and an affected preterm newborn who died within the first week of life with Neu-Laxova syndrome-2 (NLS2; 616038), all from … (more)
In 2 affected stillborn fetuses and an affected preterm newborn who died within the first week of life with Neu-Laxova syndrome-2 (NLS2; 616038), all from different families, Acuna-Hidalgo et al. (2014) identified a homozygous c.296C-T transition in the PSAT1 gene, resulting in an ala99-to-val (A99V) substitution at a highly conserved residue. The mutation was found by detailed reanalysis of exome sequencing data from the first patient; it was not correctly identified by initial exome sequencing because of its proximity to a known SNP. An affected newborn from a fourth family was found to be compound heterozygous for A99V and S179L (610936.0005). All 4 families originated from the Middle East and had either Iranian or Turkish ancestry, suggesting a founder effect that was confirmed by haplotype analysis in 2 Turkish families. The mutation was not found in the Exome Variant Server database; functional studies of the variant were not performed. (less)
|
|
|
not provided
(-)
|
no classification provided
Method: research, in vivo
|
not provided
Affected status: unknown, not applicable
Allele origin:
unknown,
not applicable
|
Dudley Research Group, Pacific Northwest Research Institute
Accession: SCV001430349.2
First in ClinVar: Aug 21, 2020 Last updated: Aug 21, 2020 |
Observation 1: Observation 2:
Comment on evidence:
Equally or more impaired in assay than known disease alleles D100A and A99V.
Method: Relative growth in yeast complementation assay. Null and wt values set to 0% and 100%, respectively.
Result:
57.773% +/- 1.822 (SE)
Observation 3:
Comment on evidence:
Equally or more impaired in assay than known disease allele D100A.
Method: Relative growth in yeast complementation assay. Null and wt values set to 0% and 100%, respectively.
Result:
62.029% +/- 2.988 (SE)
|
Comment:
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. |
|---|---|---|---|---|
|
loss_of_function_variant
|
Method citation(s):
Method citation(s):
|
|
Dudley Research Group, Pacific Northwest Research Institute
Accession: SCV001430349.2
|
Comment:
Equally or more impaired than known disease allele D100A. PMID:32077105 Table S7.
|
Comment:
Based on the classification scheme VCGS_Germline_v1.3.3, 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 Neu-Laxova syndrome 2 (MIM#616038). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to valine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD v2 <0.01 for a recessive condition (43 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated aminotransferase class-V domain (PDB). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic and likely pathogenic, in multiple homozygous and compound heterozygous patients with Neu-Laxova syndrome. As a common polymorphism is sometimes found in cis with this variant, it has also been reported as c.296_297delinsTG (ClinVar, PMID: 25152457, PMID: 26960553; PMID: 30293248). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Yeast growth assays demonstrate that this variant significantly impairs growth compared to wildtype (PMID: 32077105). (SP) 1206 - This variant has been shown to be paternally inherited (VCGS #20G001772). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| A yeast-based complementation assay elucidates the functional impact of 200 missense variants in human PSAT1. | Sirr A | Journal of inherited metabolic disease | 2020 | PMID: 32077105 |
| Contribution of next generation sequencing in pediatric practice in Lebanon. A Study on 213 cases. | Nair P | Molecular genetics & genomic medicine | 2018 | PMID: 30293248 |
| On the phenotypic spectrum of serine biosynthesis defects. | El-Hattab AW | Journal of inherited metabolic disease | 2016 | PMID: 26960553 |
| Neu-Laxova syndrome is a heterogeneous metabolic disorder caused by defects in enzymes of the L-serine biosynthesis pathway. | Acuna-Hidalgo R | American journal of human genetics | 2014 | PMID: 25152457 |
Text-mined citations for rs587777778 ...
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 Mar 17, 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.