This variant disrupts a canonical splice site and is predicted to result in abnormal splicing. Aberrant splicing and/or loss of function is an established mechanism of disease. This prediction has been confirmed by an mRNA study (PMID: 17667967). Different variants at the same splice site have been reported in association with disease and are independently classified as likely pathogenic or pathogenic. This variant has been reported in multiple individuals with paraganglioma (PMID: 12658451, 16249420, 22517554, 17667967, 34439371, 33748650). This variant is absent from or rare in large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/).
ClinVar Genomic variation as it relates to human health
NM_003001.5(SDHC):c.405+1G>T
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.
(8)
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
8
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_003001.5(SDHC):c.405+1G>T
Variation ID: 7242 Accession: VCV000007242.35
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 1q23.3 1: 161356841 (GRCh38) [ NCBI UCSC ] 1: 161326631 (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 Feb 25, 2017 Oct 20, 2024 Mar 1, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_003001.5:c.405+1G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_001035511.3:c.242-5488G>T intron variant NM_001035512.3:c.303+1G>T splice donor NM_001035513.3:c.246+1G>T splice donor NM_001278172.3:c.140-5488G>T intron variant NM_001407115.1:c.525+1G>T splice donor NM_001407116.1:c.348+1G>T splice donor NM_001407117.1:c.342+1G>T splice donor NM_001407118.1:c.297+1G>T splice donor NM_001407119.1:c.294+1G>T splice donor NM_001407120.1:c.294+1G>T splice donor NM_001407121.1:c.185-5488G>T intron variant NC_000001.11:g.161356841G>T NC_000001.10:g.161326631G>T NG_012767.1:g.47466G>T NG_157433.1:g.231G>T LRG_317:g.47466G>T LRG_317t1:c.405+1G>T - Protein change
- -
- Other names
-
IVS5, G-T, +1
- Canonical SPDI
- NC_000001.11:161356840:G:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
exon loss; Variation Ontology [ VariO:0381] PubMed: 12658451
-
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) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
- 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. |
|||
| SDHC | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
861 | 903 | |
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
|
- | RCV000007664.8 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 28, 2023 | RCV000574152.6 | |
| Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Mar 1, 2024 | RCV000681938.24 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 31, 2023 | RCV000641917.9 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 5, 2024 | RCV003996080.2 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: not provided
|
Paragangliomas 3
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Human Genetics, University Hospital of Duesseldorf
Accession: SCV004171145.1
First in ClinVar: Dec 02, 2023 Last updated: Dec 02, 2023 |
|
|
|
Pathogenic
(Jan 05, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary pheochromocytoma-paraganglioma
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004836106.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
|
Comment:
This variant disrupts a canonical splice site and is predicted to result in abnormal splicing. Aberrant splicing and/or loss of function is an established mechanism … (more)
This variant disrupts a canonical splice site and is predicted to result in abnormal splicing. Aberrant splicing and/or loss of function is an established mechanism of disease. This prediction has been confirmed by an mRNA study (PMID: 17667967). Different variants at the same splice site have been reported in association with disease and are independently classified as likely pathogenic or pathogenic. This variant has been reported in multiple individuals with paraganglioma (PMID: 12658451, 16249420, 22517554, 17667967, 34439371, 33748650). This variant is absent from or rare in large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). (less)
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Sep 12, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV005202016.1
First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024 |
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; … (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 significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 36387130, 22517554, 16249420, 32621582, 25808178, 12658451) (less)
|
|
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Pathogenic
(Dec 31, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Paragangliomas 3
Gastrointestinal stromal tumor
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000763567.5
First in ClinVar: May 28, 2018 Last updated: Feb 28, 2024 |
Comment:
This sequence change affects a donor splice site in intron 5 of the SDHC gene. RNA analysis indicates that disruption of this splice site induces … (more)
This sequence change affects a donor splice site in intron 5 of the SDHC gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely disrupts the C-terminus of the protein. This variant is present in population databases (rs587776653, gnomAD 0.002%). Disruption of this splice site has been observed in individuals with paraganglioma or gastrointestinal stromal tumor (PMID: 12658451, 16249420, 22517554). ClinVar contains an entry for this variant (Variation ID: 7242). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site results in skipping of exon 5 and introduces a new termination codon (PMID: 12658451; Invitae). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Dec 28, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000675103.5
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
The c.405+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 5 of the SDHC gene. This mutation has … (more)
The c.405+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 5 of the SDHC gene. This mutation has been reported in multiple individuals diagnosed with a head and neck paraganglioma (Niemann S et al. Hum. Genet., 2003 Jul;113:92-4; Schiavi F et al. JAMA, 2005 Oct;294:2057-63; Lefebvre S et al. Horm Metab Res, 2012 May;44:334-8). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
|
|
|
Likely pathogenic
(Mar 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV002062843.20
First in ClinVar: Jan 29, 2022 Last updated: Oct 20, 2024 |
Comment:
SDHC: PVS1:Strong, PM2, PS4:Moderate, PS3:Supporting
Number of individuals with the variant: 2
|
|
|
Likely pathogenic
(Sep 16, 2018)
|
no assertion criteria provided
Method: research
|
not provided
Affected status: yes
Allele origin:
germline
|
Gharavi Laboratory, Columbia University
Accession: SCV000809424.1
First in ClinVar: Oct 01, 2018 Last updated: Oct 01, 2018 |
|
|
|
Pathogenic
(Nov 01, 2000)
|
no assertion criteria provided
Method: literature only
|
PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 3
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000027865.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 21, 2023 |
Comment on evidence:
Niemann et al. (2003) described a 31-year-old female patient with hypotension and tachycardia. Whole body MRI showed a highly vascularized tumor at the right carotid … (more)
Niemann et al. (2003) described a 31-year-old female patient with hypotension and tachycardia. Whole body MRI showed a highly vascularized tumor at the right carotid bifurcation. The diagnosis of paraganglioma (PPGL3; 605373) was confirmed histopathologically in the tumor, and a lymph node showed metastatic tissue. Sequence analysis of the patient's constitutive DNA revealed a heterozygous G-to-T transversion at position +1 of intron 5 of the SDHC gene. An identical germline mutation was observed in the patient's mother. A high resolution computed tomography of the neck, thorax, and abdomen, and urinary excretion of catecholamines in the patient's mother were normal. The mutation led to a deletion of exon 5 and a shift in the reading frame. (less)
|
Comment:
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 at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 36387130, 22517554, 16249420, 32621582, 25808178, 12658451)
Comment:
This sequence change affects a donor splice site in intron 5 of the SDHC gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely disrupts the C-terminus of the protein. This variant is present in population databases (rs587776653, gnomAD 0.002%). Disruption of this splice site has been observed in individuals with paraganglioma or gastrointestinal stromal tumor (PMID: 12658451, 16249420, 22517554). ClinVar contains an entry for this variant (Variation ID: 7242). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site results in skipping of exon 5 and introduces a new termination codon (PMID: 12658451; Invitae). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Comment:
The c.405+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 5 of the SDHC gene. This mutation has been reported in multiple individuals diagnosed with a head and neck paraganglioma (Niemann S et al. Hum. Genet., 2003 Jul;113:92-4; Schiavi F et al. JAMA, 2005 Oct;294:2057-63; Lefebvre S et al. Horm Metab Res, 2012 May;44:334-8). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
SDHC: PVS1:Strong, PM2, PS4:Moderate, PS3:Supporting
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:
This variant disrupts a canonical splice site and is predicted to result in abnormal splicing. Aberrant splicing and/or loss of function is an established mechanism of disease. This prediction has been confirmed by an mRNA study (PMID: 17667967). Different variants at the same splice site have been reported in association with disease and are independently classified as likely pathogenic or pathogenic. This variant has been reported in multiple individuals with paraganglioma (PMID: 12658451, 16249420, 22517554, 17667967, 34439371, 33748650). This variant is absent from or rare in large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/).
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 at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 36387130, 22517554, 16249420, 32621582, 25808178, 12658451)
Comment:
This sequence change affects a donor splice site in intron 5 of the SDHC gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely disrupts the C-terminus of the protein. This variant is present in population databases (rs587776653, gnomAD 0.002%). Disruption of this splice site has been observed in individuals with paraganglioma or gastrointestinal stromal tumor (PMID: 12658451, 16249420, 22517554). ClinVar contains an entry for this variant (Variation ID: 7242). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site results in skipping of exon 5 and introduces a new termination codon (PMID: 12658451; Invitae). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Comment:
The c.405+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 5 of the SDHC gene. This mutation has been reported in multiple individuals diagnosed with a head and neck paraganglioma (Niemann S et al. Hum. Genet., 2003 Jul;113:92-4; Schiavi F et al. JAMA, 2005 Oct;294:2057-63; Lefebvre S et al. Horm Metab Res, 2012 May;44:334-8). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
SDHC: PVS1:Strong, PM2, PS4:Moderate, PS3:Supporting
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Analytical Performance of NGS-Based Molecular Genetic Tests Used in the Diagnostic Workflow of Pheochromocytoma/Paraganglioma. | Sarkadi B | Cancers | 2021 | PMID: 34439371 |
| Head and Neck Paragangliomas: Patterns of Otolaryngology Referrals for Genetic Testing Over 2 Decades. | Smith JD | OTO open | 2021 | PMID: 33748650 |
| Screening of mutations in genes that predispose to hereditary paragangliomas and pheochromocytomas. | Lefebvre S | Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme | 2012 | PMID: 22517554 |
| Clinical and molecular genetics of patients with the Carney-Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD. | Pasini B | European journal of human genetics : EJHG | 2008 | PMID: 17667967 |
| 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 |
| Predictors and prevalence of paraganglioma syndrome associated with mutations of the SDHC gene. | Schiavi F | JAMA | 2005 | PMID: 16249420 |
| Autosomal dominant malignant and catecholamine-producing paraganglioma caused by a splice donor site mutation in SDHC. | Niemann S | Human genetics | 2003 | PMID: 12658451 |
| Mutations in SDHC cause autosomal dominant paraganglioma, type 3. | Niemann S | Nature genetics | 2000 | PMID: 11062460 |
| Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
Text-mined citations for rs587776653 ...
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 Oct 20, 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.