ClinVar Genomic variation as it relates to human health
NM_003001.5(SDHC):c.377A>G (p.Tyr126Cys)
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.377A>G (p.Tyr126Cys)
Variation ID: 428933 Accession: VCV000428933.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q23.3 1: 161356812 (GRCh38) [ NCBI UCSC ] 1: 161326602 (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 Sep 15, 2017 Apr 15, 2024 Jan 25, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003001.5:c.377A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002992.1:p.Tyr126Cys missense NM_001035511.3:c.242-5517A>G intron variant NM_001035512.3:c.275A>G NP_001030589.1:p.Tyr92Cys missense NM_001035513.3:c.218A>G NP_001030590.1:p.Tyr73Cys missense NM_001278172.3:c.140-5517A>G intron variant NM_001407115.1:c.497A>G NP_001394044.1:p.Tyr166Cys missense NM_001407116.1:c.320A>G NP_001394045.1:p.Tyr107Cys missense NM_001407117.1:c.314A>G NP_001394046.1:p.Tyr105Cys missense NM_001407118.1:c.269A>G NP_001394047.1:p.Tyr90Cys missense NM_001407119.1:c.266A>G NP_001394048.1:p.Tyr89Cys missense NM_001407120.1:c.266A>G NP_001394049.1:p.Tyr89Cys missense NM_001407121.1:c.185-5517A>G intron variant NR_103459.3:n.429A>G non-coding transcript variant NC_000001.11:g.161356812A>G NC_000001.10:g.161326602A>G NG_012767.1:g.47437A>G LRG_317:g.47437A>G LRG_317t1:c.377A>G LRG_317p1:p.Tyr126Cys - Protein change
- Y126C, Y73C, Y92C, Y105C, Y166C, Y90C, Y107C, Y89C
- Other names
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- Canonical SPDI
- NC_000001.11:161356811: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) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00004
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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 |
825 | 867 |
Conditions - Germline
Condition
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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
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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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Likely pathogenic (1) |
criteria provided, single submitter
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Jun 12, 2023 | RCV000492617.8 | |
Pathogenic (1) |
no assertion criteria provided
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- | RCV000505370.3 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Mar 22, 2023 | RCV000523379.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 25, 2024 | RCV000551177.9 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 28, 2023 | RCV002286411.4 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Sep 27, 2023 | RCV003419827.4 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jul 29, 2023 | RCV003476182.1 |
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
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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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Likely pathogenic
(Mar 22, 2023)
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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: SCV000619404.6
First in ClinVar: Dec 19, 2017 Last updated: Apr 01, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.Y97C; This variant is associated with the following publications: (PMID: 34558728, 29305721, 15989954, 36672771) (less)
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Likely pathogenic
(Jun 12, 2023)
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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: SCV000581216.6
First in ClinVar: Jul 01, 2017 Last updated: Jul 08, 2023 |
Comment:
The p.Y126C variant (also known as c.377A>G), located in coding exon 5 of the SDHC gene, results from an A to G substitution at nucleotide … (more)
The p.Y126C variant (also known as c.377A>G), located in coding exon 5 of the SDHC gene, results from an A to G substitution at nucleotide position 377. The tyrosine at codon 126 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in multiple individuals with paragangliomas (Ambry internal data; Lozano Sánchez et al. Angiología. 2010;62(6):214-218; Sen I et al. J Vasc Surg, 2020 May;71:1602-1612.e2; Williams ST et al. Clin Endocrinol (Oxf), 2022 Apr;96:499-512). Based on internal structural analysis, the tyrosine is located near the hemi-binding center and is part of the SQR domain in the SDHC protein; this variant is predicted to destabilize protein structure more than known remote pathogenic variants (Sun F et al. Cell. 2005 Jul;121:1043-57). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
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Likely pathogenic
(Sep 27, 2023)
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criteria provided, single submitter
Method: clinical testing
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SDHC-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004109276.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The SDHC c.377A>G variant is predicted to result in the amino acid substitution p.Tyr126Cys. This variant has been reported in five unrelated individuals with head … (more)
The SDHC c.377A>G variant is predicted to result in the amino acid substitution p.Tyr126Cys. This variant has been reported in five unrelated individuals with head and neck paraganglioma (Lozano Sánchez et al. 2010. Angiologia. 62(6): 214-18. https://doi.org/10.1016/S0003-3170(10)70051-1; Table S1, Verginelli et al. 2018. PubMed ID: 29305721; Supplement, Sen et al. 2020. PubMed ID: 32035780; Tables 3 and S3, Williams et al. 2022. PubMed ID: 34558728). It has also been reported as a likely pathogenic, paternally-inherited secondary finding in a pediatric individual with a neurodevelopmental indication (Table 1, Halfmeyer et al. 2022. PubMed ID: 36672771). This variant is predicted to be protein destabilizing (Williams et al. 2022. PubMed ID: 34558728). This variant has not been reported in a large population database (https://gnomad.broadinstitute.org/), indicating this variant is rare. This variant has been reported in ClinVar as likely pathogenic and pathogenic by outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/428933/). This variant is interpreted as likely pathogenic. (less)
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Likely pathogenic
(Jul 29, 2023)
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criteria provided, single submitter
Method: clinical testing
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Gastrointestinal stromal tumor
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004203070.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Likely pathogenic
(Nov 28, 2023)
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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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Color Diagnostics, LLC DBA Color Health
Accession: SCV004362297.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces tyrosine with cysteine at codon 126 of the SDHC protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces tyrosine with cysteine at codon 126 of the SDHC protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in multiple individuals affected with paraganglioma (PMID: 19245779, 29305721, 32035780, 34558728). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
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Pathogenic
(Jan 25, 2024)
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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: SCV000641438.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 126 of the SDHC protein … (more)
This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 126 of the SDHC protein (p.Tyr126Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with paragangliomas (Invitae). ClinVar contains an entry for this variant (Variation ID: 428933). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Aug 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Paragangliomas 3
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
paternal
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV002576447.2
First in ClinVar: Oct 01, 2022 Last updated: Apr 15, 2024 |
Clinical Features:
Motor delay (present) , Orofacial cleft (present) , Obesity (present) , Global developmental delay (present) , Tall stature (present) , Seizure (present) , Gray matter … (more)
Motor delay (present) , Orofacial cleft (present) , Obesity (present) , Global developmental delay (present) , Tall stature (present) , Seizure (present) , Gray matter heterotopia (present) , Delayed speech and language development (present) (less)
Sex: female
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Pathogenic
(-)
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no assertion criteria provided
Method: research
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Hereditary pheochromocytoma-paraganglioma
Affected status: yes
Allele origin:
germline
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Section on Medical Neuroendocrinolgy, National Institutes of Health
Accession: SCV000599554.1
First in ClinVar: Sep 15, 2017 Last updated: Sep 15, 2017 |
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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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SDHC phaeochromocytoma and paraganglioma: A UK-wide case series. | Williams ST | Clinical endocrinology | 2022 | PMID: 34558728 |
Tumor-specific prognosis of mutation-positive patients with head and neck paragangliomas. | Sen I | Journal of vascular surgery | 2020 | PMID: 32035780 |
Paragangliomas arise through an autonomous vasculo-angio-neurogenic program inhibited by imatinib. | Verginelli F | Acta neuropathologica | 2018 | PMID: 29305721 |
[Surgical treatment of carotid paragangliomas]. | Lozano Sánchez FS | Acta otorrinolaringologica espanola | 2009 | PMID: 19245779 |
Crystal structure of mitochondrial respiratory membrane protein complex II. | Sun F | Cell | 2005 | PMID: 15989954 |
Text-mined citations for rs898854295 ...
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.