ClinVar Genomic variation as it relates to human health
NM_003001.5(SDHC):c.1A>G (p.Met1Val)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_003001.5(SDHC):c.1A>G (p.Met1Val)
Variation ID: 407060 Accession: VCV000407060.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q23.3 1: 161314406 (GRCh38) [ NCBI UCSC ] 1: 161284196 (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, 2017 Feb 28, 2024 Dec 26, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003001.5:c.1A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002992.1:p.Met1Val missense initiator codon variant NM_001035511.3:c.1A>G NP_001030588.1:p.Met1Val missense NM_001035512.3:c.1A>G NP_001030589.1:p.Met1Val missense NM_001035513.3:c.1A>G NP_001030590.1:p.Met1Val missense NM_001278172.3:c.1A>G NP_001265101.1:p.Met1Val missense NM_001407115.1:c.1A>G NP_001394044.1:p.Met1Val missense NM_001407116.1:c.1A>G NP_001394045.1:p.Met1Val missense NM_001407117.1:c.1A>G NP_001394046.1:p.Met1Val missense NM_001407118.1:c.1A>G NP_001394047.1:p.Met1Val missense NM_001407119.1:c.-560A>G NM_001407120.1:c.-229A>G NM_001407121.1:c.1A>G NP_001394050.1:p.Met1Val missense NR_103459.3:n.26A>G NC_000001.11:g.161314406A>G NC_000001.10:g.161284196A>G NG_008055.1:g.567T>C NG_012767.1:g.5031A>G LRG_256:g.567T>C LRG_317:g.5031A>G LRG_317t1:c.1A>G LRG_317p1:p.Met1Val - Protein change
- M1V
- Other names
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- Canonical SPDI
- NC_000001.11:161314405:A:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
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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SDHC | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
834 | 876 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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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Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Feb 8, 2023 | RCV000467345.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 21, 2022 | RCV000492170.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 26, 2023 | RCV000791400.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 31, 2021 | RCV001559453.4 |
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
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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
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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
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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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Pathogenic
(Nov 01, 2016)
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criteria provided, single submitter
Method: clinical testing
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Paragangliomas 3
Affected status: yes
Allele origin:
germline
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Center for Human Genetics, Inc, Center for Human Genetics, Inc
Accession: SCV000782281.2
First in ClinVar: Jul 07, 2018 Last updated: Sep 03, 2023 |
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Pathogenic
(Oct 12, 2018)
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criteria provided, single submitter
Method: clinical testing
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Paragangliomas 3
Affected status: unknown
Allele origin:
germline
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Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV001434947.2
First in ClinVar: Oct 03, 2020 Last updated: Sep 03, 2023 |
Comment:
This rare c.1A>G (p.Met1?) variant (seen once in gnomAD) in the SDHC gene is predicted to result in a start codon loss of the major … (more)
This rare c.1A>G (p.Met1?) variant (seen once in gnomAD) in the SDHC gene is predicted to result in a start codon loss of the major biological transcripts. The variant has been observed in multiple unrelated individuals paraganglioma/pheochromocytoma (PMID 16249420, 19351833, 19454582). Predicted start codon loss with different nucleotide changes in this gene has been also observed in other individuals with paraganglioma (PMID : 19351833) . Therefore, this c.1A>G (p.Met1?) variant variant is considered as pathogenic. (less)
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Pathogenic
(Jul 17, 2020)
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criteria provided, single submitter
Method: clinical testing
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Paragangliomas 3
Affected status: unknown
Allele origin:
germline
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New York Genome Center
Study: CSER-NYCKidSeq
Accession: SCV001622967.2 First in ClinVar: May 21, 2021 Last updated: Sep 03, 2023 |
Comment:
The variant c.1A>G affects the initiator methionine of the SDHC mRNA. This variant is present in population databases (gnomAD v30.001%) and has been reported in … (more)
The variant c.1A>G affects the initiator methionine of the SDHC mRNA. This variant is present in population databases (gnomAD v30.001%) and has been reported in the literature in 3 individuals affected with paraganglioma/pheochromocytoma and gastrointestinal stromal tumors [PMID: 23282968; PMID: 22517554; PMID: 19454582], and in a family with Paraganglioma Syndrome [PMID: 16249420]. Two different variants (c.2T>A and c.3G>A) that disrupt the same methionine initiator have been reported in patients and families affected with head and neck paragangliomas [PMID: 19351833], paragangliomas [PMID: 11062460], and renal cell carcinoma [PMID: 22351710], indicating that this methionine initiator of SDHC may be critical for protein function. Based on the available evidence, this variant has been classified as Pathogenic. (less)
Clinical Features:
Intellectual disability (present) , Autism (present)
Secondary finding: yes
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Pathogenic
(Mar 31, 2021)
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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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GeneDx
Accession: SCV001781683.2
First in ClinVar: Aug 14, 2021 Last updated: Sep 03, 2023 |
Comment:
Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts … (more)
Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31589614, 31447099, 16249420, 28748451, 19351833, 23282968, 19454582, 22517557, 27011036) (less)
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Pathogenic
(Apr 21, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000581217.6
First in ClinVar: Jul 01, 2017 Last updated: Sep 03, 2023 |
Comment:
The p.M1? pathogenic mutation (also known as c.1A>G) is located in coding exon 1 of the SDHC gene and results from an A to G … (more)
The p.M1? pathogenic mutation (also known as c.1A>G) is located in coding exon 1 of the SDHC gene and results from an A to G substitution at nucleotide position 1. This alters the methionine residue at the initiation codon. This mutation has previously been reported in multiple individuals diagnosed with paragangliomas (Schiavi F et al. JAMA. 2005 Oct;294:2057-63; Burnichon N et al. J. Clin. Endocrinol. Metab. 2009 Aug;94:2817-27; Neumann HP et al. Cancer Res. 2009 Apr;69:3650-6; Am J Surg Pathol 2013 Feb;37(2):234-40; Niemann S et al. Nat Genet 2000 Nov;26(3):268-70). The mutation was also detected in an individual whose GIST tumor showed a loss of SDHB expression and intact SDHA expression on IHC (Miettinen M et al. Am. J. Surg. Pathol. 2013 Feb;37:234-40). In addition to the clinical data presented in the literature, sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(Feb 08, 2023)
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criteria provided, single submitter
Method: clinical testing
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Paragangliomas 3
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV004018724.2
First in ClinVar: Jul 29, 2023 Last updated: Sep 03, 2023 |
Comment:
This variant is considered pathogenic. This variant is located within the gene translation start codon (p.Met1?) and is predicted to result in abnormal protein translation. … (more)
This variant is considered pathogenic. This variant is located within the gene translation start codon (p.Met1?) and is predicted to result in abnormal protein translation. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 30201732, 30877234, 16249420, 11062460, 24096523]. (less)
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Pathogenic
(Dec 26, 2023)
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criteria provided, single submitter
Method: clinical testing
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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
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Invitae
Accession: SCV000546039.9
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change affects the initiator methionine of the SDHC mRNA. The next in-frame methionine is located at codon 38. This variant is present in … (more)
This sequence change affects the initiator methionine of the SDHC mRNA. The next in-frame methionine is located at codon 38. This variant is present in population databases (rs755235380, gnomAD 0.006%). Disruption of the initiator codon has been observed in individuals with clinical features of SDHC-related conditions (PMID: 11062460, 16249420, 19454582, 22351710, 22517554, 23282968). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 407060). For these reasons, this variant has been classified as Pathogenic. (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Targeted next-generation sequencing detects rare genetic events in pheochromocytoma and paraganglioma. | Ben Aim L | Journal of medical genetics | 2019 | PMID: 30877234 |
Bayesian approach to determining penetrance of pathogenic SDH variants. | Benn DE | Journal of medical genetics | 2018 | PMID: 30201732 |
Non-pheochromocytoma (PCC)/paraganglioma (PGL) tumors in patients with succinate dehydrogenase-related PCC-PGL syndromes: a clinicopathological and molecular analysis. | Papathomas TG | European journal of endocrinology | 2013 | PMID: 24096523 |
Immunohistochemical loss of succinate dehydrogenase subunit A (SDHA) in gastrointestinal stromal tumors (GISTs) signals SDHA germline mutation. | Miettinen M | The American journal of surgical pathology | 2013 | PMID: 23282968 |
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 |
Biallelic inactivation of the SDHC gene in renal carcinoma associated with paraganglioma syndrome type 3. | Malinoc A | Endocrine-related cancer | 2012 | PMID: 22351710 |
The succinate dehydrogenase genetic testing in a large prospective series of patients with paragangliomas. | Burnichon N | The Journal of clinical endocrinology and metabolism | 2009 | PMID: 19454582 |
Clinical predictors for germline mutations in head and neck paraganglioma patients: cost reduction strategy in genetic diagnostic process as fall-out. | Neumann HP | Cancer research | 2009 | PMID: 19351833 |
Predictors and prevalence of paraganglioma syndrome associated with mutations of the SDHC gene. | Schiavi F | JAMA | 2005 | PMID: 16249420 |
Mutations in SDHC cause autosomal dominant paraganglioma, type 3. | Niemann S | Nature genetics | 2000 | PMID: 11062460 |
Text-mined citations for rs755235380 ...
HelpRecord last updated Apr 15, 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.