ClinVar Miner

Submissions for variant NM_003000.3(SDHB):c.749C>T (p.Thr250Ile)

gnomAD frequency: 0.00001  dbSNP: rs1057517537
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000412001 SCV000487862 uncertain significance Paragangliomas 4 2015-11-23 criteria provided, single submitter clinical testing
Ambry Genetics RCV000565120 SCV000675087 uncertain significance Hereditary cancer-predisposing syndrome 2024-06-15 criteria provided, single submitter clinical testing The p.T250I variant (also known as c.749C>T), located in coding exon 7 of the SDHB gene, results from a C to T substitution at nucleotide position 749. The threonine at codon 250 is replaced by isoleucine, an amino acid with similar properties. 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000694160 SCV000822591 uncertain significance Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2023-10-05 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 250 of the SDHB protein (p.Thr250Ile). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SDHB-related conditions. ClinVar contains an entry for this variant (Variation ID: 371792). 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 not expected to disrupt SDHB protein function. 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.
Neuberg Centre For Genomic Medicine, NCGM RCV001823137 SCV002073204 uncertain significance Mitochondrial complex 2 deficiency, nuclear type 4 criteria provided, single submitter clinical testing The missense variant p.T250I in SDHB (NM_003000.3) has been submitted to ClinVar as Uncertain Significance. It has not been reported previously in affected individuals. The p.T250I variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. There is a moderate physicochemical difference between threonine and isoleucine. The p.T250I missense variant is predicted to be damaging by both SIFT and PolyPhen2. The threonine residue at codon 250 of SDHB is conserved in all mammalian species. The nucleotide c.749 in SDHB is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.
Sema4, Sema4 RCV000565120 SCV002527092 uncertain significance Hereditary cancer-predisposing syndrome 2022-01-30 criteria provided, single submitter curation
Baylor Genetics RCV004567895 SCV005056633 uncertain significance Gastrointestinal stromal tumor 2024-02-06 criteria provided, single submitter clinical testing

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