ClinVar Miner

Submissions for variant NM_003000.3(SDHB):c.769C>G (p.Leu257Val)

gnomAD frequency: 0.00001  dbSNP: rs761350633
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Mendelics RCV000708779 SCV000837727 uncertain significance Cowden syndrome 2018-07-02 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000819850 SCV000960532 uncertain significance Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2023-02-14 criteria provided, single submitter clinical testing This missense change has been observed in individual(s) with clinical features of mitochondrial complex II deficiency (PMID: 27604842, 34490615). 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. 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 SDHB protein function. ClinVar contains an entry for this variant (Variation ID: 584582). This variant is present in population databases (rs761350633, gnomAD 0.0009%). This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 257 of the SDHB protein (p.Leu257Val).
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV002268269 SCV002552218 pathogenic not provided 2023-08-15 criteria provided, single submitter clinical testing
Ambry Genetics RCV004659188 SCV005161196 uncertain significance Hereditary cancer-predisposing syndrome 2024-04-02 criteria provided, single submitter clinical testing The p.L257V variant (also known as c.769C>G), located in coding exon 8 of the SDHB gene, results from a C to G substitution at nucleotide position 769. The leucine at codon 257 is replaced by valine, an amino acid with highly similar properties. This alteration has been identified as homozygous in patients with mitochondrial complex II deficiency (Grønborg S et al. JIMD Rep, 2017 Sep;33:69-77; van der Ven AT et al. Clin Genet, 2021 Dec;100:766-770). 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 majority of available evidence to date, this variant is lexpected to be causative of autosomal recessive mitochondrial complex II deficiency when present along with a second likely pathogenic/pathogenic variant on the other allele; however, its clinical significance in regards to autosomal dominant paraganglioma-pheochromocytoma syndrome is unclear.
OMIM RCV001310279 SCV001500012 pathogenic Mitochondrial complex 2 deficiency, nuclear type 4 2021-03-08 no assertion criteria provided literature only

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