VCV000984624.33 - ClinVar

NM_016955.4(SEPSECS):c.114+3A>G

Germline

Classification

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.

(6)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_016955.4(SEPSECS):c.114+3A>G

Variation ID: 984624 Accession: VCV000984624.33

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 4p15.2 4: 25160253 (GRCh38) [ NCBI UCSC ] 4: 25161875 (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	Nov 12, 2020	Jun 29, 2024	Jun 18, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_016955.4:c.114+3A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NC_000004.12:g.25160253T>C
NC_000004.11:g.25161875T>C
NG_028222.1:g.5330A>G

Protein change

Other names

Canonical SPDI

NC_000004.12:25160252:T:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Links

VarSome

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
Gene	OMIM	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.
LOC129992330	-	-	-	GRCh38	-	38
SEPSECS		-	-	GRCh38 GRCh37	551	616

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.
Neurodevelopmental abnormality	Uncertain significance (1)	no assertion criteria provided	Aug 14, 2020	RCV001264723.8
not provided	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jan 13, 2024	RCV001281617.14
Pontoneocerebellar hypoplasia	Likely pathogenic (1)	criteria provided, single submitter	Jul 25, 2023	RCV003323838.8
Pontocerebellar hypoplasia type 2D	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jun 18, 2024	RCV003387987.2

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 (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	Laboratoire de Génétique Moléculaire, CHU Bordeaux Accession: SCV001468946.1 First in ClinVar: Jan 17, 2021 Last updated: Jan 17, 2021
Pathogenic (Jan 13, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002190740.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 34234304‚ 35012964‚ 17576681‚ 9536098 Comment: This sequence change falls in intron 1 of the SEPSECS gene. It does not directly change the encoded amino acid sequence of the SEPSECS protein. … (more) This sequence change falls in intron 1 of the SEPSECS gene. It does not directly change the encoded amino acid sequence of the SEPSECS protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs748528138, gnomAD 0.02%). This variant has been observed in individuals with SEPSECS-related conditions (PMID: 34234304, 35012964; Invitae). ClinVar contains an entry for this variant (Variation ID: 984624). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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)
Pathogenic (Apr 27, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Pontocerebellar hypoplasia type 2D Affected status: yes Allele origin: germline	Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL) Accession: SCV003920815.1 First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023	Number of individuals with the variant: 2
Likely pathogenic (Jul 25, 2023)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Pontoneocerebellar hypoplasia Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV004029171.1 First in ClinVar: Aug 26, 2023 Last updated: Aug 26, 2023	Publications: PubMed (6) PubMed: 34234304‚ 31748115‚ 32555262‚ 35155316‚ 35012964‚ 36085396 Comment: Variant summary: SEPSECS c.114+3A>G alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly … (more) Variant summary: SEPSECS c.114+3A>G alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5 splicing donor site. Two predict the variant weakens a 5' donor site. In addition, at least one minigene splicing assay revealed this variant results in skipping of exon 1 (Schlter_2022). However, one splicing assay reported cDNA sample from blood cells does not observe alteration in the splicing (Arrudi-Moreno_2021). The variant allele was found at a frequency of 4.6e-05 in 151924 control chromosomes (gnomAD). c.114+3A>G has been reported in the literature in compound heterozygous and homozygous individuals affected with Pontocerebellar Hypoplasia, Type 2D, inherited ataxia or genetic white matter disorders (Benkirane_2021, Arrudi-Moreno_2021, Schlter_2022). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. The following publications have been ascertained in the context of this evaluation (PMID: 34234304, 32555262, 35155316, 35012964, 36085396, 31748115). Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
Likely pathogenic (Jun 18, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Pontocerebellar hypoplasia type 2D (Autosomal recessive inheritance) Affected status: yes Allele origin: paternal	Medical Genetics Laboratory, University of Catania Accession: SCV005061756.1 First in ClinVar: Jun 29, 2024 Last updated: Jun 29, 2024	Publications: DOI: 10.3389/fped.2021.805575 DOI: 10.3389/fped.2021.805575 Clinical Features: Pontocerebellar atrophy (present) Age: 0-9 years Sex: male Ethnicity/Population group: caucasian Geographic origin: Italy
Uncertain significance (Aug 14, 2020)	no assertion criteria provided Method: clinical testing	Neurodevelopmental abnormality Affected status: yes Allele origin: inherited	Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine Accession: SCV001442954.1 First in ClinVar: Nov 12, 2020 Last updated: Nov 12, 2020	Sex: male

Comment:

This sequence change falls in intron 1 of the SEPSECS gene. It does not directly change the encoded amino acid sequence of the SEPSECS protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs748528138, gnomAD 0.02%). This variant has been observed in individuals with SEPSECS-related conditions (PMID: 34234304, 35012964; Invitae). ClinVar contains an entry for this variant (Variation ID: 984624). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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.

Comment:

Variant summary: SEPSECS c.114+3A>G alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5 splicing donor site. Two predict the variant weakens a 5' donor site. In addition, at least one minigene splicing assay revealed this variant results in skipping of exon 1 (Schlter_2022). However, one splicing assay reported cDNA sample from blood cells does not observe alteration in the splicing (Arrudi-Moreno_2021). The variant allele was found at a frequency of 4.6e-05 in 151924 control chromosomes (gnomAD). c.114+3A>G has been reported in the literature in compound heterozygous and homozygous individuals affected with Pontocerebellar Hypoplasia, Type 2D, inherited ataxia or genetic white matter disorders (Benkirane_2021, Arrudi-Moreno_2021, Schlter_2022). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. The following publications have been ascertained in the context of this evaluation (PMID: 34234304, 32555262, 35155316, 35012964, 36085396, 31748115). Based on the evidence outlined above, the variant was classified as likely 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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Analysis of the Clinical Features and Imaging Findings of Pontocerebellar Hypoplasia Type 2D Caused by Mutations in SEPSECS Gene.	Zhao R	Cerebellum (London, England)	2023	PMID: 36085396
Case Report: A Relatively Mild Phenotype Produced by Novel Mutations in the SEPSECS Gene.	Rong T	Frontiers in pediatrics	2022	DOI: 10.3389/fped.2021.805575
Case Report: A Relatively Mild Phenotype Produced by Novel Mutations in the SEPSECS Gene.	Rong T	Frontiers in pediatrics	2022	PMID: 35155316
Diagnosis of Genetic White Matter Disorders by Singleton Whole-Exome and Genome Sequencing Using Interactome-Driven Prioritization.	Schlüter A	Neurology	2022	PMID: 35012964
High rate of hypomorphic variants as the cause of inherited ataxia and related diseases: study of a cohort of 366 families.	Benkirane M	Genetics in medicine : official journal of the American College of Medical Genetics	2021	PMID: 34234304
A new mutation in the SEPSECS gene related to pontocerebellar hypoplasia type 2D.	Arrudi-Moreno M	Medicina clinica	2021	PMID: 31748115
Single Circulating Fetal Trophoblastic Cells Eligible for Non Invasive Prenatal Diagnosis: the Exception Rather than the Rule.	Cayrefourcq L	Scientific reports	2020	PMID: 32555262
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.	Buratti E	Nucleic acids research	2007	PMID: 17576681
Statistical features of human exons and their flanking regions.	Zhang MQ	Human molecular genetics	1998	PMID: 9536098

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_016955.4(SEPSECS):c.114+3A>G

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...