ClinVar Genomic variation as it relates to human health
NM_003002.4(SDHD):c.335C>T (p.Thr112Ile)
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_003002.4(SDHD):c.335C>T (p.Thr112Ile)
Variation ID: 239468 Accession: VCV000239468.26
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q23.1 11: 112094825 (GRCh38) [ NCBI UCSC ] 11: 111965549 (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 Apr 9, 2017 Feb 28, 2024 Jan 11, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003002.4:c.335C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002993.1:p.Thr112Ile missense NM_001276503.2:c.190C>T NP_001263432.1:p.Leu64= synonymous NM_001276504.2:c.218C>T NP_001263433.1:p.Thr73Ile missense NM_001276506.2:c.*33C>T 3 prime UTR NR_077060.2:n.424C>T non-coding transcript variant NC_000011.10:g.112094825C>T NC_000011.9:g.111965549C>T NG_012337.3:g.12979C>T LRG_9:g.12979C>T LRG_9t1:c.335C>T LRG_9p1:p.Thr112Ile - Protein change
- T112I, T73I
- Other names
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- Canonical SPDI
- NC_000011.10:112094824:C:T
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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
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
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
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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
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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SDHD | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
631 | 764 |
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
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. |
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Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jan 1, 2019 | RCV000455598.17 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Aug 16, 2022 | RCV000760070.16 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000764954.10 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 27, 2023 | RCV001020081.11 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 11, 2024 | RCV002229661.11 |
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
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. |
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Uncertain significance
(Jun 16, 2016)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000540307.1
First in ClinVar: Apr 09, 2017 Last updated: Apr 09, 2017 |
Comment:
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or … (more)
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 1 family that also carried Q109X, and T112I did not segregate with disease. (less)
Method: Genome/Exome Filtration
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Uncertain significance
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Paragangliomas 1
Pheochromocytoma Mitochondrial complex II deficiency, nuclear type 1 Carney-Stratakis syndrome
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000896127.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Uncertain significance
(Jan 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
unknown
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Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV000923664.1
First in ClinVar: Jun 17, 2019 Last updated: Jun 17, 2019 |
Number of individuals with the variant: 1
Sex: male
Geographic origin: Iran
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Uncertain significance
(Mar 06, 2018)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000889835.3
First in ClinVar: Mar 14, 2019 Last updated: Dec 31, 2022 |
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Uncertain significance
(Aug 16, 2022)
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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: SCV001757397.3
First in ClinVar: Jul 24, 2021 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate mixed results regarding this variant's effect on the function of the SDHD protein (Panizza et al., 2013); In silico analysis supports … (more)
Published functional studies demonstrate mixed results regarding this variant's effect on the function of the SDHD protein (Panizza et al., 2013); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17308434, 30093976, 17102085, 28975465, 31666924, 16061558, 32035780, 32504289, 23175444) (less)
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Uncertain significance
(Feb 27, 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: SCV001181512.4
First in ClinVar: Mar 16, 2020 Last updated: Apr 15, 2023 |
Comment:
The p.T112I variant (also known as c.335C>T), located in coding exon 4 of the SDHD gene, results from a C to T substitution at nucleotide … (more)
The p.T112I variant (also known as c.335C>T), located in coding exon 4 of the SDHD gene, results from a C to T substitution at nucleotide position 335. The threonine at codon 112 is replaced by isoleucine, an amino acid with similar properties. This alteration has been reported in an individual with pheochromocytoma as well as an individual with a head and neck paraganglioma (Mannelli M et al. Ann. N. Y. Acad. Sci. 2006 Aug;1073:183-9; Albattal S et al. Oncotarget. 2019 Oct;10:5919-5931). This alteration was also reported in a large PGL/PCC family in conjunction with an SDHD nonsense mutation (Q109*). The one individual affected with a neural crest tumor in this family harbored the Q109* alteration and not p.T112I; several unaffected individuals also carried the p.T112I alteration (Simi L et al. J. Med. Genet. 2005 Aug;42:e52). This alteration has also been reported in a woman diagnosed with early-onset breast cancer as well as two individuals diagnosed with papillary thyroid cancer (Chan GHJ et al. Oncotarget. 2018 Jul;9:30649-30660; Siraj AK et al. Hum Genet. 2017 11;136:1431-1444). One yeast functional study showed that p.T112I reduces SDH enzyme activity by 50% and increases mtDNA mutability, but it does not affect oxidative growth (Panizza E et al. Hum. Mol. Genet. 2013 Feb;22:804-15). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Jan 11, 2024)
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criteria provided, single submitter
Method: clinical testing
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Carney-Stratakis syndrome
Paragangliomas with sensorineural hearing loss Pheochromocytoma Cowden syndrome 3
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: SCV000287824.9
First in ClinVar: Jul 01, 2016 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 112 of the SDHD protein (p.Thr112Ile). … (more)
This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 112 of the SDHD protein (p.Thr112Ile). This variant is present in population databases (rs199869408, gnomAD 0.006%). This missense change has been observed in individual(s) with paraganglioma, thyroid cancer, breast cancer, and pheochromocytoma (PMID: 17102085, 28975465, 30093976, 31666924). ClinVar contains an entry for this variant (Variation ID: 239468). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SDHD protein function. Experimental studies have shown that this missense change affects SDHD function (PMID: 23175444). 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. (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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Mutational profile and genotype/phenotype correlation of non-familial pheochromocytoma and paraganglioma. | Albattal S | Oncotarget | 2019 | PMID: 31666924 |
Clinical genetic testing outcome with multi-gene panel in Asian patients with multiple primary cancers. | Chan GHJ | Oncotarget | 2018 | PMID: 30093976 |
Expanding the spectrum of germline variants in cancer. | Siraj AK | Human genetics | 2017 | PMID: 28975465 |
Yeast model for evaluating the pathogenic significance of SDHB, SDHC and SDHD mutations in PHEO-PGL syndrome. | Panizza E | Human molecular genetics | 2013 | PMID: 23175444 |
SDH mutations in patients affected by paraganglioma syndromes: a personal experience. | Mannelli M | Annals of the New York Academy of Sciences | 2006 | PMID: 17102085 |
Phenotype variability of neural crest derived tumours in six Italian families segregating the same founder SDHD mutation Q109X. | Simi L | Journal of medical genetics | 2005 | PMID: 16061558 |
Text-mined citations for rs199869408 ...
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.