ClinVar Genomic variation as it relates to human health
NM_003002.4(SDHD):c.340T>G (p.Tyr114Asp)
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
-
NM_003002.4(SDHD):c.340T>G (p.Tyr114Asp)
Variation ID: 993407 Accession: VCV000993407.8
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 11q23.1 11: 112094830 (GRCh38) [ NCBI UCSC ] 11: 111965554 (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 Jan 26, 2021 Nov 29, 2022 Nov 3, 2020 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_003002.4:c.340T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002993.1:p.Tyr114Asp missense NM_001276503.2:c.195T>G NP_001263432.1:p.Thr65= synonymous NM_001276504.2:c.223T>G NP_001263433.1:p.Tyr75Asp missense NM_001276506.2:c.*38T>G 3 prime UTR NR_077060.2:n.429T>G non-coding transcript variant NC_000011.10:g.112094830T>G NC_000011.9:g.111965554T>G NG_012337.3:g.12984T>G LRG_9:g.12984T>G LRG_9t1:c.340T>G LRG_9p1:p.Tyr114Asp - Protein change
- Y114D, Y75D
- Other names
- -
- Canonical SPDI
- NC_000011.10:112094829:T: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.
-
- 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. |
|||
SDHD | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
- | 764 |
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) |
criteria provided, single submitter
|
Dec 23, 2019 | RCV001812309.13 | |
Pathogenic (1) |
criteria provided, single submitter
|
Nov 3, 2020 | RCV002451642.8 |
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
(Dec 23, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001471048.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
Comment:
The SDHD c.340T>G; p.Tyr114Asp variant, to our knowledge, is not reported in the medical literature or gene specific databases. This variant is also absent from … (more)
The SDHD c.340T>G; p.Tyr114Asp variant, to our knowledge, is not reported in the medical literature or gene specific databases. This variant is also absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The tyrosine at codon 114 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, a different variant at this codon (Tyr114Cys) is reported in multiple individuals and families affected with pheochromocytoma or paraganlioma (Andrews 2018, Antonello 2008, Benn 2006, Braun 2005, Fish 2007, Milunsky 2001, Neumann 2004, Piccini 2012, Richter 2019), and is a common variant in Italy due to a founder effect (Schiavi 2012). Functional analyses in yeast demonstrate that the Tyr114 residue (Tyr89 in yeast) is essential for ubiquinone reductase activity (Silkin 2007). Based on available information, the p.Tyr114Asp variant is considered to be likely pathogenic. REFERENCES Andrews KA et al. Tumour risks and genotype-phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes SDHB, SDHC and SDHD. J Med Genet. 2018 Jun;55(6):384-394. Antonello M et al. Role of the genetic study in the management of carotid body tumor in paraganglioma syndrome. Eur J Vasc Endovasc Surg. 2008 Nov;36(5):517-9. Benn DE et al. Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes. J Clin Endocrinol Metab. 2006 Mar;91(3):827-36. Braun S et al. Active succinate dehydrogenase (SDH) and lack of SDHD mutations in sporadic paragangliomas. Anticancer Res. 2005 Jul-Aug;25(4):2809-14. Fish JH et al. Systematic screening and treatment evaluation of hereditary neck paragangliomas. Head Neck. 2007 Sep;29(9):864-73. Milunsky JM et al. Novel mutations and the emergence of a common mutation in the SDHD gene causing familial paraganglioma. Am J Med Genet. 2001 May 15;100(4):311-4. Neumann HP et al. Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. JAMA. 2004 Aug 25;292(8):943-51. Piccini V et al. Head and neck paragangliomas: genetic spectrum and clinical variability in 79 consecutive patients. Endocr Relat Cancer. 2012 Apr 10;19(2):149-55. Richter S et al. Metabolome-guided genomics to identify pathogenic variants in isocitrate dehydrogenase, fumarate hydratase, and succinate dehydrogenase genes in pheochromocytoma and paraganglioma. Genet Med. 2019 Mar;21(3):705-717. Schiavi F et al. The endemic paraganglioma syndrome type 1: origin, spread, and clinical expression. J Clin Endocrinol Metab. 2012 Apr;97(4):E637-41. Silkin Y et al. The role of Sdh4p Tyr-89 in ubiquinone reduction by the Saccharomyces cerevisiae succinate dehydrogenase. Biochim Biophys Acta. 2007 Feb;1767(2):143-50. (less)
|
|
Pathogenic
(Nov 03, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002614372.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.Y114D pathogenic mutation (also known as c.340T>G), located in coding exon 4 of the SDHD gene, results from a T to G substitution at … (more)
The p.Y114D pathogenic mutation (also known as c.340T>G), located in coding exon 4 of the SDHD gene, results from a T to G substitution at nucleotide position 340. The tyrosine at codon 114 is replaced by aspartic acid, an amino acid with highly dissimilar properties. Internal structural analysis shows that p.Y114D is on an interface, is part of a known functional motif, and is moderately destabilizing to the local structure (Ambry internal data). Two other alterations at the same codon, p.Y114N (c.340T>A) and p.Y114C (c.341A>G), have been detected in numerous individuals affected with paragangliomas and/or pheochromocytomas (Neumann H et al. JAMA. 2004 Aug 25;292(8):943-51; Liapis C et al. Anticancer Res. 2005 May-Jun;25(3c):2449-52; Benn D et al. J. Clin. Endocrinol. Metab. 2006 Mar;91(3):827-36; Antonello M et al. Eur. J. Vasc. Endovasc. Surg. 2008 Nov;36(5):517-9; Piccini V et al. Endocr. Relat. Cancer. 2012 Apr 10;19(2):149-55; Zdrojowy-Wena A and Bednarek-Tupikowska G. Neuro Endocrinol. Lett. 2014;35(5):355-8; Bennedbæk M et al. Hered. Cancer Clin. Pract. 2016 Jun;14:13; Schiavi F et al. J Clin Endocrinol. Merab 2012;97(4):637-41). This variant was not reported in population-based 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
|
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
HelpThere are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar. |
Text-mined citations for rs876659276 ...
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.