ClinVar Genomic variation as it relates to human health
NM_018359.5(UFSP2):c.344T>A (p.Val115Glu)
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.
Pathogenic(7); Likely pathogenic(3); Uncertain significance(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_018359.5(UFSP2):c.344T>A (p.Val115Glu)
Variation ID: 932944 Accession: VCV000932944.59
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 4q35.1 4: 185415857 (GRCh38) [ NCBI UCSC ] 4: 186337011 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Dec 19, 2020 Aug 4, 2024 Mar 25, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_018359.5:c.344T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_060829.2:p.Val115Glu missense NM_018359.4:c.344T>A NR_028085.2:n.415T>A non-coding transcript variant NR_144317.2:n.440T>A non-coding transcript variant NC_000004.12:g.185415857A>T NC_000004.11:g.186337011A>T NG_051609.1:g.15129T>A - Protein change
- V115E
- Other names
- UFSP2, VAL115GLU (rs142500730)
- Canonical SPDI
- NC_000004.12:185415856:A:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- effect on protein abundance Variation Ontology [VariO:0052]
- Decreased function
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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.
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0.00040 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
The Genome Aggregation Database (gnomAD), exomes 0.00013
Exome Aggregation Consortium (ExAC) 0.00018
1000 Genomes Project 30x 0.00031
1000 Genomes Project 0.00040
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 | ||
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HI score
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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. |
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CFAP96 | - | - | - |
GRCh38 GRCh37 |
5 | 162 |
UFSP2 | - | - |
GRCh38 GRCh37 |
21 | 181 |
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. |
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Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Jan 1, 2022 | RCV001815509.23 | |
Pathogenic (1) |
no assertion criteria provided
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Dec 30, 2020 | RCV001270480.5 | |
UFSP2-related neurodevelopmental disorder
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Pathogenic (2) |
criteria provided, single submitter
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Mar 22, 2022 | RCV002051920.6 |
Pathogenic (1) |
criteria provided, single submitter
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Jun 11, 2021 | RCV001843571.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 1, 2023 | RCV003163507.5 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Mar 25, 2024 | RCV003988863.3 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Oct 1, 2021 | RCV001727845.4 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jul 10, 2021 | RCV001814280.4 | |
Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Nov 29, 2023 | RCV002281647.15 |
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. |
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Likely pathogenic
(Jul 10, 2021)
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criteria provided, single submitter
Method: clinical testing
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Abnormality of the nervous system
Affected status: yes
Allele origin:
germline
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Kariminejad - Najmabadi Pathology & Genetics Center
Accession: SCV001755244.1
First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022 |
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Likely pathogenic
(Oct 01, 2021)
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criteria provided, single submitter
Method: clinical testing
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Focal-onset seizure
Severe global developmental delay Epileptic encephalopathy
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001976429.1
First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
Comment:
This variant was identified as homozygous.
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Pathogenic
(Jun 11, 2021)
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criteria provided, single submitter
Method: clinical testing
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Olivopontocerebellar hypoplasia
Affected status: yes
Allele origin:
inherited
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Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine
Accession: SCV002102956.1
First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022 |
Sex: female
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Pathogenic
(Mar 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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UFSP2-related neurodevelopmental disorder
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002318584.1
First in ClinVar: Apr 02, 2022 Last updated: Apr 02, 2022 |
Comment:
The variant was co-segregated with UFSP2-related neurodevelopmental disorder and epilepsy in multiple affected family members (PMID: 33473208). The variant has been observed in multiple (>3) … (more)
The variant was co-segregated with UFSP2-related neurodevelopmental disorder and epilepsy in multiple affected family members (PMID: 33473208). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 33473208). Functional assays showed that the variant had moderate level of impact on gene/protein function (PMID: 33473208). A missense variant is a common mechanism. It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency:0.0001279). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Seizure (present) , Intellectual disability (present)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy 106
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Accession: SCV002576342.1
First in ClinVar: Oct 08, 2022 Last updated: Oct 08, 2022 |
Age: 0-9 years
Sex: female
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Uncertain significance
(Sep 02, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002203431.2
First in ClinVar: Mar 28, 2022 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces valine with glutamic acid at codon 115 of the UFSP2 protein (p.Val115Glu). The valine residue is moderately conserved and there is … (more)
This sequence change replaces valine with glutamic acid at codon 115 of the UFSP2 protein (p.Val115Glu). The valine residue is moderately conserved and there is a moderate physicochemical difference between valine and glutamic acid. This variant is present in population databases (rs142500730, ExAC 0.1%). This missense change has been observed in individual(s) with UFSP2-related conditions (PMID: 33473208). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 932944). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Pathogenic
(Mar 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy, 1
Affected status: no
Allele origin:
germline
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Payam Genetics Center, General Welfare Department of North Khorasan Province
Accession: SCV003915428.1
First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023
Comment:
The UFSP2 c.344T>A mutation (p.Val115Glu) is a missense mutation and its result is a disfunctional protien, predicted lead to Spondyloepimetaphyseal dysplasia Di Rocco type.This variant … (more)
The UFSP2 c.344T>A mutation (p.Val115Glu) is a missense mutation and its result is a disfunctional protien, predicted lead to Spondyloepimetaphyseal dysplasia Di Rocco type.This variant is not present in population databases (ExAC no frequency) , was not found in 1000G, Genom AD exome, and Iranom. This variant has not been reported in the literature in individuals affected with UFSP2-related conditions. This variant predicted as Pathogenic according to ACMG. (less)
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Number of individuals with the variant: 4
Sex: mixed
Ethnicity/Population group: Iranian
Geographic origin: Iran
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Pathogenic
(Mar 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy 106
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004041012.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
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Pathogenic
(Nov 29, 2023)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy 106
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
inherited
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Centre for Inherited Metabolic Diseases, Karolinska University Hospital
Accession: SCV004171204.1
First in ClinVar: Dec 02, 2023 Last updated: Dec 02, 2023 |
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Likely pathogenic
(Mar 25, 2024)
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criteria provided, single submitter
Method: research
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Hip dysplasia, Beukes type
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004805375.2
First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024 |
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Developmental and epileptic encephalopathy 106
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004048539.4
First in ClinVar: Oct 28, 2023 Last updated: Jul 15, 2024 |
Comment:
The observed missense variant c.344T>A (p.Val115Glu) in UFSP2 gene has been reported in homozygous state in multiple individuals affected with UFSP2-associated epilepsy syndrome. Experimental evidence … (more)
The observed missense variant c.344T>A (p.Val115Glu) in UFSP2 gene has been reported in homozygous state in multiple individuals affected with UFSP2-associated epilepsy syndrome. Experimental evidence has shown that homozygosity for this variant causes UFSP2 destabilization, reduced UFSP2 expression in fibroblasts (indicating a loss of function effect), and may lead to reduced protein stability and possibly reduced interaction with UFMylated targets (Ni et al. 2021). The p.Val115Glu variant is present with an allele frequency of 0.01% in the gnomAD exomes database. This variant has been submitted to the ClinVar database as Uncertain significance / Likely Pathogenic / Pathogenic (multiple submissions). The amino acid change p.Val115Glu in UFSP2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Val at position 115 is changed to a Glu changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Abnormality of the nervous system (present)
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Uncertain significance
(Jan 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV002062567.18
First in ClinVar: Jan 29, 2022 Last updated: Aug 04, 2024 |
Number of individuals with the variant: 3
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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UFSP2-related neurodevelopmental disorder
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Accession: SCV002499638.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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Pathogenic
(Sep 07, 2022)
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no assertion criteria provided
Method: literature only
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DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 106
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV002570100.1
First in ClinVar: Sep 10, 2022 Last updated: Sep 10, 2022 |
Comment on evidence:
In 8 patients from 4 unrelated families from Pakistan and Afghanistan with developmental and epileptic encephalopathy-106 (DEE106; 620028), Ni et al. (2021) identified a homozygous … (more)
In 8 patients from 4 unrelated families from Pakistan and Afghanistan with developmental and epileptic encephalopathy-106 (DEE106; 620028), Ni et al. (2021) identified a homozygous c.344T-A transversion (c.344T-A, NM_018359) in the UFSP2 gene, resulting in a val115-to-glu (V115E) substitution at a conserved residue near the N-terminal domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Homozygosity mapping in a consanguineous family also confirmed the results. The heterozygous parents were asymptomatic. The variant was present at a low overall frequency (0.00013) in the gnomAD database (v2.1.1). Studies of patient-derived fibroblasts showed decreased levels of the UFSP2 protein, with normal mRNA levels, suggesting that the mutation causes destabilization of the protein. Patient-derived fibroblasts showed enhanced levels of UFM1-conjugated proteins. Ectopic expression of wildtype UFSP2, but not the mutant, normalized the levels of UFMylated proteins in these cells. The findings were consistent with a loss of UFSP2 function towards de-UFMylation. (less)
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Pathogenic
(Dec 30, 2020)
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no assertion criteria provided
Method: research
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Seizure
Microcephaly Intellectual disability (Autosomal recessive inheritance)
Affected status: yes, not applicable
Allele origin:
germline,
not applicable
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Genetic and Metabolic Disease Program, Children's Medical Center Research Institute, UT Southwestern Medical Center at Dallas
Accession: SCV001338803.2
First in ClinVar: Dec 19, 2020 Last updated: Jan 30, 2021 |
Observation 1:
Number of individuals with the variant: 8
Clinical Features:
Global developmental delay (present) , Intellectual disability (present) , Seizure (present) , Microcephaly (present)
Age: 2-11 years
Sex: mixed
Ethnicity/Population group: Pakistani, Afghanistani
Observation 2:
Sex: mixed
Tissue: skin
Result:
The UFSP2 protein is significantly decreased in the fibroblast lines derived from the skin biopsy samples of three patients with this homozygous variant.
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Pathogenic
(Dec 15, 2022)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
unknown
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Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare
Accession: SCV004175134.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
Clinical Features:
seizure (present) , global developmental delay (present) , Microcephaly (present) , hypotonia (present) , dystonia (present) , hearing impairment (present) , visual impairment (present)
Age: 0-9 years
Sex: female
Ethnicity/Population group: South East Asian
Geographic origin: Bangladesh
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Likely pathogenic
(Nov 09, 2023)
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no assertion criteria provided
Method: research
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Developmental and epileptic encephalopathy 106
(Autosomal recessive inheritance)
Affected status: yes, no
Allele origin:
germline
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Department of Biotechnology and Genetic Engineering, Kohat University of Science and Technology
Accession: SCV004174819.1
First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023 |
Comment:
The UFSP2 gene encodes a cysteine protease that participates in Ubiquitin-fold modifier 1 (UFM1) maturation in a process known as UFMylation and also releases UFM1 … (more)
The UFSP2 gene encodes a cysteine protease that participates in Ubiquitin-fold modifier 1 (UFM1) maturation in a process known as UFMylation and also releases UFM1 from UFMylated proteins in a process known as de-UFMylation. Both UFMylation and de-UFMylation are processes of post-translational protein modification, and functional studies have revealed that the loss of key components of these processes results in defects in embryogenesis, hematopoiesis, cellular differentiation, and brain development. Pathogenic variants (p.D426A, p.H428R, p.(Cys302Ser)) in two of the three components of the catalytic triad (Asp426 and His428) have already been associated with patients with different types of skeletal dysplasia. Homozygous variants (p.Val115Glu) were found to cause drug-refractory epilepsy and other brain defects. Specifically, p.Val115Glu was found to cause drug-refractory epilepsy and DD, whereas the Val115Glu variant was detected in patients with drug-refractory epilepsy, infantile spasms, and severe ID. In the current study, the p.Val115Glu variant was found to cause drug-refractory epilepsy, DD, ID, and anxiety in patients of a Pakistani family. Previous study findings suggested that variants observed in human skeletal dysplasia impact UFSP2's catalytic activity, whereas the homozygous p.Val115Glu variant found associated with brain defects impacts the N-terminal domain, including protein stability and interaction with UFMylated targets (PMID: 33473208). (less)
Observation 1:
Number of individuals with the variant: 2
Sex: mixed
Observation 2:
Number of individuals with the variant: 2
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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. |
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Decreased function
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Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Accession: SCV002576342.1
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effect on protein abundance
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Genetic and Metabolic Disease Program, Children's Medical Center Research Institute, UT Southwestern Medical Center at Dallas
Accession: SCV001338803.2
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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A pathogenic UFSP2 variant in an autosomal recessive form of pediatric neurodevelopmental anomalies and epilepsy. | Ni M | Genetics in medicine : official journal of the American College of Medical Genetics | 2021 | PMID: 33473208 |
Text-mined citations for rs142500730 ...
HelpRecord last updated Aug 04, 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.