ClinVar Genomic variation as it relates to human health
NM_016955.4(SEPSECS):c.846G>A (p.Leu282=)
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(1); Likely pathogenic(2); Uncertain significance(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_016955.4(SEPSECS):c.846G>A (p.Leu282=)
Variation ID: 522806 Accession: VCV000522806.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 4p15.2 4: 25145092 (GRCh38) [ NCBI UCSC ] 4: 25146714 (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 Apr 29, 2018 Feb 20, 2024 Nov 17, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_016955.4:c.846G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_058651.3:p.Leu282= synonymous NC_000004.12:g.25145092C>T NC_000004.11:g.25146714C>T NG_028222.1:g.20491G>A - Protein change
- Other names
- -
- Canonical SPDI
- NC_000004.12:25145091:C: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 RNA splicing Variation Ontology [VariO:0362]
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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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0.00020 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00003
The Genome Aggregation Database (gnomAD) 0.00004
Exome Aggregation Consortium (ExAC) 0.00005
Trans-Omics for Precision Medicine (TOPMed) 0.00005
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
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
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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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SEPSECS | - | - |
GRCh38 GRCh37 |
550 | 615 |
Conditions - Germline
Condition
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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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Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Oct 12, 2021 | RCV000625975.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 17, 2023 | RCV001462752.7 | |
Uncertain significance (1) |
criteria provided, single submitter
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Aug 2, 2021 | RCV001553762.1 |
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. |
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Likely pathogenic
(Apr 06, 2017)
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criteria provided, single submitter
Method: clinical testing
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Pontocerebellar hypoplasia type 2D
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
maternal
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Undiagnosed Diseases Network, NIH
Accession: SCV000746576.2
First in ClinVar: Apr 29, 2018 Last updated: Apr 29, 2018 |
Comment:
The c.846G>A variant in SEPSECS was shown to result in exon skipping by RNAseq. The variant is present in 6 individuals in gnomAD as heterozygotes. … (more)
The c.846G>A variant in SEPSECS was shown to result in exon skipping by RNAseq. The variant is present in 6 individuals in gnomAD as heterozygotes. The variant was identifed as a compound heterozygote with c.808dupG that is a frameshift variant. (less)
Number of individuals with the variant: 1
Clinical Features:
Stridor (present) , Sleep disturbance (present) , Severe muscular hypotonia (present) , Severe global developmental delay (present) , Reduced visual acuity (present) , Ptosis (present) … (more)
Stridor (present) , Sleep disturbance (present) , Severe muscular hypotonia (present) , Severe global developmental delay (present) , Reduced visual acuity (present) , Ptosis (present) , Poor head control (present) , Poor appetite (present) , Nystagmus (present) , Myopathic facies (present) , Muscle weakness (present) , Irritability (present) , Intellectual disability (present) , Hypoplasia of the corpus callosum (present) , Hypopigmentation of the fundus (present) , Hypoglycemia (present) , Hyperhidrosis (present) , Hand clenching (present) , Gastrostomy tube feeding in infancy (present) , Feeding difficulties (present) , Failure to thrive (present) , Exotropia (present) , EEG with persistent abnormal rhythmic activity (present) , Dyskinesia (present) , Decreased urine output (present) , Cortical visual impairment (present) , Cerebral hypoplasia (present) , Cerebral hypomyelination (present) , Cerebral atrophy (present) , Breathing dysregulation (present) , Abnormality of the vocal cords (present) , Abnormality of the optic disc (present) , Abnormality of the cerebral cortex (present) (less)
Age: 0-9 years
Sex: female
Ethnicity/Population group: White
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Uncertain significance
(Aug 02, 2021)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001774756.1
First in ClinVar: Aug 07, 2021 Last updated: Aug 07, 2021 |
Comment:
Variant summary: SEPSECS c.846G>A alters a conserved nucleotide resulting in a synonymous change. 4/4 computational tools predict no significant impact on normal splicing. The variant … (more)
Variant summary: SEPSECS c.846G>A alters a conserved nucleotide resulting in a synonymous change. 4/4 computational tools predict no significant impact on normal splicing. The variant allele was found at a frequency of 2.8e-05 in 250948 control chromosomes. c.846G>A has been reported in the literature in a 2-year-old female with severe hypotonia, global developmental delay with cerebral atrophy, hypomyelination, and central volume loss of the cerebrum who underwent trio genome sequencing and trio RNAseq from blood (Lee_2020). The patient was found to carry a paternal frameshift variant in SEPSECS (c.808dup) while the variant of interest was found on the maternal allele. RNAseq analysis showed the 130-bp exon 7 containing the synonymous variant (p. Leu282=) was skipped in about half of the mRNAs. The novel splice junction that joins exon 6 and exon 8 was detected in 25/695 additional unrelated samples without this variant, but at a much lower ratio compared with our proband and mother, suggesting that exon 7 may be susceptible to low-level skipping. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic, and one laboratory classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. (less)
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Likely pathogenic
(Oct 01, 2021)
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criteria provided, single submitter
Method: research
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Pontocerebellar hypoplasia type 2D
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
paternal
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Institute for Genomic Medicine, Nationwide Children's Hospital
Accession: SCV001960821.1
First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
Comment:
This variant was identified in two siblings with PCH type 2D and was compound-heterozygous with an initiator codon variant (c.1A>T) considered to be pathogenic. Although … (more)
This variant was identified in two siblings with PCH type 2D and was compound-heterozygous with an initiator codon variant (c.1A>T) considered to be pathogenic. Although the c.846G>A is a synonymous change, it has been shown to disrupt splicing in experimental work by the UDN (PMID: 31607746). It is extremely rare (AF~0.00004) with no homozygotes reported in public databases including gnomAD and TopMed. We interpret the variant as likely pathogenic. (less)
Clinical Features:
Generalized hypotonia (present) , Delayed gross motor development (present) , Global developmental delay (present) , Microcephaly (present) , Seizure (present)
Sex: female
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Uncertain significance
(Oct 12, 2021)
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criteria provided, single submitter
Method: clinical testing
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Pontocerebellar hypoplasia type 2D
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003819332.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Nov 17, 2023)
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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: SCV001666677.4
First in ClinVar: Jun 08, 2021 Last updated: Feb 20, 2024 |
Comment:
This sequence change affects codon 282 of the SEPSECS mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid … (more)
This sequence change affects codon 282 of the SEPSECS mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the SEPSECS protein. This variant is present in population databases (rs146539065, gnomAD 0.02%). This variant has been observed in individual(s) with pontocerebellar hypoplasia (PMID: 31607746, 35091508). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 522806). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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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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effect on RNA splicing
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Institute for Genomic Medicine, Nationwide Children's Hospital
Accession: SCV001960821.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Biallelic SEPSECS variants in two siblings with pontocerebellar hypoplasia type 2D underscore the relevance of splice-disrupting synonymous variants in disease. | Ramadesikan S | Cold Spring Harbor molecular case studies | 2022 | PMID: 35091508 |
Diagnostic utility of transcriptome sequencing for rare Mendelian diseases. | Lee H | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 31607746 |
Text-mined citations for rs146539065 ...
HelpRecord last updated Jul 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.