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NM_003002.4(SDHD):c.335C>T (p.Thr112Ile) AND Hereditary cancer-predisposing syndrome

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Feb 27, 2023
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV001020081.11

Allele description [Variation Report for NM_003002.4(SDHD):c.335C>T (p.Thr112Ile)]

NM_003002.4(SDHD):c.335C>T (p.Thr112Ile)

Gene:
SDHD:succinate dehydrogenase complex subunit D [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
11q23.1
Genomic location:
Preferred name:
NM_003002.4(SDHD):c.335C>T (p.Thr112Ile)
HGVS:
  • NC_000011.10:g.112094825C>T
  • NG_012337.3:g.12979C>T
  • NM_001276503.2:c.190C>T
  • NM_001276504.2:c.218C>T
  • NM_001276506.2:c.*33C>T
  • NM_003002.4:c.335C>TMANE SELECT
  • NP_001263432.1:p.Leu64=
  • NP_001263433.1:p.Thr73Ile
  • NP_002993.1:p.Thr112Ile
  • LRG_9t1:c.335C>T
  • LRG_9:g.12979C>T
  • LRG_9p1:p.Thr112Ile
  • NC_000011.9:g.111965549C>T
  • NM_003002.2:c.335C>T
  • NM_003002.3:c.335C>T
  • NR_077060.2:n.424C>T
Protein change:
T112I
Links:
dbSNP: rs199869408
NCBI 1000 Genomes Browser:
rs199869408
Molecular consequence:
  • NM_001276506.2:c.*33C>T - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
  • NM_001276504.2:c.218C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_003002.4:c.335C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NR_077060.2:n.424C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NM_001276503.2:c.190C>T - synonymous variant - [Sequence Ontology: SO:0001819]

Condition(s)

Name:
Hereditary cancer-predisposing syndrome
Synonyms:
Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001181512Ambry Genetics
criteria provided, single submitter

(Ambry General Variant Classification Scheme_2022)		Uncertain significance
(Feb 27, 2023) 		germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Phenotype variability of neural crest derived tumours in six Italian families segregating the same founder SDHD mutation Q109X.

Simi L, Sestini R, Ferruzzi P, Gaglianò MS, Gensini F, Mascalchi M, Guerrini L, Pratesi C, Pinzani P, Nesi G, Ercolino T, Genuardi M, Mannelli M.

J Med Genet. 2005 Aug;42(8):e52.

PubMed [citation]
PMID:
16061558
PMCID:
PMC1736123

SDH mutations in patients affected by paraganglioma syndromes: a personal experience.

Mannelli M, Simi L, Ercolino T, Gaglianò MS, Becherini L, Vinci S, Sestini R, Gensini F, Pinzani P, Mascalchi M, Guerrini L, Pratesi C, Nesi G, Torti F, Cipollini F, Bernini GP, Genuardi M.

Ann N Y Acad Sci. 2006 Aug;1073:183-9.

PubMed [citation]
PMID:
17102085
See all PubMed Citations (6)

Details of each submission

From Ambry Genetics, SCV001181512.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Apr 20, 2024