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

dbSNP: rs727504457

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000155443	SCV000205134	likely pathogenic	Hereditary pheochromocytoma-paraganglioma	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: http://evs.gs.washington.edu/EVS/). 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	pathogenic	Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma	2023-02-01	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 87 of the SDHB protein (p.Leu87Ser). This missense change has been observed in individuals with paragangliomas and/or pheochromocytomas (PMID: 11404820, 12807974, 15328326, 19454582, 22517557; Invitae). For these reasons, this variant has been classified as Pathogenic. 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: 178686). This variant is also known as 394T>C (L88S) and 263T>C (L88S).
Ambry Genetics	RCV001016096	SCV001177011	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-10	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 variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Myriad Genetics, Inc.	RCV003315943	SCV004018746	likely pathogenic	Paragangliomas 4	2023-02-08	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 12807974, 31492822, 15328326]. This variant is expected to disrupt protein structure [internal Myriad data].