ClinVar Genomic variation as it relates to human health
NM_003001.5(SDHC):c.379C>G (p.His127Asp)
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); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_003001.5(SDHC):c.379C>G (p.His127Asp)
Variation ID: 1677290 Accession: VCV001677290.6
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 1q23.3 1: 161356814 (GRCh38) [ NCBI UCSC ] 1: 161326604 (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 Apr 23, 2022 Feb 28, 2024 May 10, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_003001.5:c.379C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002992.1:p.His127Asp missense NM_001035511.3:c.242-5515C>G intron variant NM_001035512.3:c.277C>G NP_001030589.1:p.His93Asp missense NM_001035513.3:c.220C>G NP_001030590.1:p.His74Asp missense NM_001278172.3:c.140-5515C>G intron variant NM_001407115.1:c.499C>G NP_001394044.1:p.His167Asp missense NM_001407116.1:c.322C>G NP_001394045.1:p.His108Asp missense NM_001407117.1:c.316C>G NP_001394046.1:p.His106Asp missense NM_001407118.1:c.271C>G NP_001394047.1:p.His91Asp missense NM_001407119.1:c.268C>G NP_001394048.1:p.His90Asp missense NM_001407120.1:c.268C>G NP_001394049.1:p.His90Asp missense NM_001407121.1:c.185-5515C>G intron variant NR_103459.3:n.431C>G non-coding transcript variant NC_000001.11:g.161356814C>G NC_000001.10:g.161326604C>G NG_012767.1:g.47439C>G LRG_317:g.47439C>G LRG_317t1:c.379C>G LRG_317p1:p.His127Asp - Protein change
- H127D, H74D, H93D, H167D, H90D, H91D, H106D, H108D
- Other names
- -
- Canonical SPDI
- NC_000001.11:161356813:C:G
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
- 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 |
- | 867 |
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. |
---|---|---|---|---|
Likely pathogenic (1) |
no assertion criteria provided
|
Oct 11, 2021 | RCV002223159.3 | |
Pathogenic (1) |
criteria provided, single submitter
|
May 27, 2021 | RCV002352956.2 | |
Uncertain significance (1) |
criteria provided, single submitter
|
May 10, 2023 | RCV003101258.3 |
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
(May 27, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002620134.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.H127D pathogenic mutation (also known as c.379C>G), located in coding exon 5 of the SDHC gene, results from a C to G substitution at … (more)
The p.H127D pathogenic mutation (also known as c.379C>G), located in coding exon 5 of the SDHC gene, results from a C to G substitution at nucleotide position 379. The histidine at codon 127 is replaced by aspartic acid, an amino acid with similar properties. This mutation has been detected in multiple individuals with paraganglioma(s) (Pczkowska M et al. Eur J Endocrinol, 2017 Feb;176:143-157; Ambry internal data). Another alteration at the same codon, p.H127R (c.380A>G), has been detected in multiple individuals with a paraganglioma, gastrointestinal stromal tumor, or renal carcinoma (Rattenberry E et al. J Clin Endocrinol Metab, 2013 Jul;98:E1248-56; Dénes J et al. J Clin Endocrinol Metab, 2015 Mar;100:E531-41; Gill AJ et al. Pathology, 2013 12;45:689-91; Casey RT et al. Sci Rep, 2019 07;9:10244). Based on internal structural analysis, p.H127D disrupts the SDHC heme-binding site, within which there are other internally pathogenic variants (Sun F et al. Cell, 2005 Jul;121:1043-57; Fufezan C et al. Proteins, 2008 Nov;73:690-704; Lemarie A et al. Mitochondrion, 2009 Jul;9:254-60). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
|
|
Uncertain significance
(May 10, 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
|
Invitae
Accession: SCV002977324.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 28, 2024 |
Comment:
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 … (more)
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. This variant disrupts the p.His127 amino acid residue in SDHC. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22517557, 23162105, 24758179, 26273102, 30050099). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SDHC protein function. ClinVar contains an entry for this variant (Variation ID: 1677290). This variant has not been reported in the literature in individuals affected with SDHC-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 127 of the SDHC protein (p.His127Asp). (less)
|
|
Likely pathogenic
(Oct 11, 2021)
|
no assertion criteria provided
Method: clinical testing
|
Paragangliomas 3
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Gemeinschaftspraxis fuer Humangenetik Dresden
Accession: SCV002500061.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Comment:
This mutation c.379C>G, p.(His127Asp) is not reported in HGMD 2021.2, gnomAD (v2.1.1), dbSNP (v151) or LOVD. But on same aminoacid position the pathogenic mutations p.(His127Tyr) … (more)
This mutation c.379C>G, p.(His127Asp) is not reported in HGMD 2021.2, gnomAD (v2.1.1), dbSNP (v151) or LOVD. But on same aminoacid position the pathogenic mutations p.(His127Tyr) and p.(His127Arg) for phenotype Phaeochromocytoma/paraganglioma are known. Multiple lines of computational evidence support a deleterious effect (SIFT, MutationTaster2021, PolyPhen-2). In summary, the p.(His127Asp) variant meets our criteria to be classified as likely pathogenic. ACMG: PM5, PM2, PP3 (ACMG Guidelines, 2015) (less)
|
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 |
---|---|---|---|---|
Metabolome-guided genomics to identify pathogenic variants in isocitrate dehydrogenase, fumarate hydratase, and succinate dehydrogenase genes in pheochromocytoma and paraganglioma. | Richter S | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 30050099 |
The clinical utility of circulating neuroendocrine gene transcript analysis in well-differentiated paragangliomas and pheochromocytomas. | Pęczkowska M | European journal of endocrinology | 2017 | PMID: 27913608 |
15 YEARS OF PARAGANGLIOMA: Clinical manifestations of paraganglioma syndromes types 1-5. | Benn DE | Endocrine-related cancer | 2015 | PMID: 26273102 |
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. | Richards S | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25741868 |
The clinical phenotype of SDHC-associated hereditary paraganglioma syndrome (PGL3). | Else T | The Journal of clinical endocrinology and metabolism | 2014 | PMID: 24758179 |
Imaging work-up for screening of paraganglioma and pheochromocytoma in SDHx mutation carriers: a multicenter prospective study from the PGL.EVA Investigators. | Gimenez-Roqueplo AP | The Journal of clinical endocrinology and metabolism | 2013 | PMID: 23162105 |
A decade (2001-2010) of genetic testing for pheochromocytoma and paraganglioma. | Buffet A | Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme | 2012 | PMID: 22517557 |
Text-mined citations for rs1485675090 ...
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.