ClinVar Miner

Submissions for variant NM_003000.3(SDHB):c.260T>C (p.Leu87Ser) (rs727504457)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000155443 SCV000205134 likely pathogenic Hereditary Paraganglioma-Pheochromocytoma Syndromes 2013-08-16 criteria provided, single submitter clinical testing The Leu87Ser variant in SDHB has been reported in at least 6 individuals with pa raganglioma/pheochromocytoma, one of which progressed into malignant disease (Bu rnichon 2009, Buffet 2012). In addition, this variant has been identified in 1 i n >13,000 control chromosomes (Astuti 2001, Neumann 2004, Burnichon 2009, NHLBI Exome Sequencing Project: Please note that f or diseases with clinical variability, reduced penetrance, or recessive inherita nce, pathogenic variants may be present at a low frequency in the general popula tion. Computational analyses (biochemical amino acid properties, conservation, A lignGVGD, PolyPhen2, and SIFT) suggest that the Leu87Ser variant may impact the protein, though this information is not predictive enough to determine pathogeni city. In summary, this variant is likely to be pathogenic based on published dat a and a low allele frequency in control chromosomes, though additional studies a re required to fully establish its clinical significance.
Invitae RCV000697957 SCV000826592 likely pathogenic Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2020-09-09 criteria provided, single submitter clinical testing This sequence change replaces leucine with serine at codon 87 of the SDHB protein (p.Leu87Ser). The leucine residue is highly conserved and there is a large physicochemical difference between leucine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals and families affected with paragangliomas and/or pheochromocytomas (PMID: 11404820, 19454582, 15328326, 22517557, 12807974, Saud Alrasheedi et al, 2010, World Journal of Endocrine Surgery, 2(1):51-52 and Invitae), as well as one healthy individual (PMID: 11404820). This variant is also known as 394T>C (L88S) and 263T>C (L88S) in the literature. ClinVar contains an entry for this variant (Variation ID: 178686). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV001016096 SCV001177011 pathogenic Hereditary cancer-predisposing syndrome 2018-11-21 criteria provided, single submitter clinical testing The p.L87S pathogenic mutation (also known as c.260T>C), located in coding exon 3 of the SDHB gene, results from a T to C substitution at nucleotide position 260. The leucine at codon 87 is replaced by serine, an amino acid with dissimilar properties. This alteration was originally reported in one study that analyzed 24 cases of sporadic pheochromocytomas, and this alteration was detected in a 55-year-old woman with a personal history of an adrenal pheochromocytoma (Astuti D et al. Am. J. Hum. Genet., 2001 Jul;69:49-54). In a subsequent study, this mutation was observed in three families with either adrenal or extra-adrenal phenochromocytoma. In one family with history of extra-adrenal phenochromocytoma, six individuals, including the index case, were found to carry this mutation. In addition, this mutation was not detected in 300 control samples from white healthy blood donors (Neumann HP et al. JAMA, 2004 Aug;292:943-51). The mutation was also reported in 1 out of 445 patients with paragangliomas, and it was not detected in 200 control chromosomes sampled (Burnichon N et al. J. Clin. Endocrinol. Metab., 2009 Aug;94:2817-27). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Sun F et al. Cell, 2005 Jul;121:1043-57). 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.

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