Submissions for variant NM_003000.3(SDHB):c.575G>A (p.Cys192Tyr)

dbSNP: rs397516835

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130852	SCV000185750	pathogenic	Hereditary cancer-predisposing syndrome	2024-05-31	criteria provided, single submitter	clinical testing	The p.C192Y pathogenic mutation (also known as c.575G>A), located in coding exon 6 of the SDHB gene, results from a G to A substitution at nucleotide position 575. The cysteine at codon 192 is replaced by tyrosine, an amino acid with highly dissimilar properties. This mutation has been reported in multiple individuals diagnosed with paraganglioma-pheochromocytoma (PGL-PCC) syndrome (Benn DE et al. J Clin Endocrinol Metab. 2006 Mar;91(3):827-36; Burnichon N et al. J Clin Endocrinol Metab. 2009 Aug;94(8):2817-27; Jochmanova I et al. J. Cancer Res. Clin. Oncol. 2017 Aug;143:1421-1435). The cysteine at codon 192 has been shown to play a vital role coordinating the iron-sulfur cluster in SDHB protein (Iverson TM et al. J Biol Chem. 2012 Oct 12;287(42):35430-8). In addition, another alteration at codon 192 (p.C192R) has been reported in two individuals, one with a sporadic pheochromocytoma and the other with a paraganglioma (Neumann HP et al. N Engl J Med. 2002 May 9;3466(19):1459-66; Burnichon N et al. J Clin Endocrinol Metab. 2009 Aug;94(8):2817-27). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002514739	SCV003522745	pathogenic	Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma	2024-09-24	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 192 of the SDHB protein (p.Cys192Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with SDHB-related conditions (PMID: 16317055, 19454582, 28374168, 34906457; internal data). ClinVar contains an entry for this variant (Variation ID: 142047). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SDHB protein function with a positive predictive value of 80%. This variant disrupts the p.Cys192 amino acid residue in SDHB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12000816, 17200167, 18382370, 22517554, 25371406, 27785149). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000505338	SCV005885265	pathogenic	Hereditary pheochromocytoma-paraganglioma	2025-02-28	criteria provided, single submitter	clinical testing	Variant summary: SDHB c.575G>A (p.Cys192Tyr) results in a non-conservative amino acid change in the encoded protein sequence. This variant affects a cysteine that has been shown to play a vital role coordinating the iron-sulfur cluster in SDHB protein (Saxena_2016). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251156 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.575G>A has been reported in the literature in individuals affected with Hereditary Paraganglioma-Pheochromocytoma Syndrome (example: Benn_2006, Burnichon_2009, Jochmanova_2017, Jochmanova_2020, Ding_2022, Tang_2024, Internal data). The following publications have been ascertained in the context of this evaluation (PMID: 16317055, 19454582, 35546442, 28374168, 32062700, 26719882, 34906457). ClinVar contains an entry for this variant (Variation ID: 142047). Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Genetics, Inc.	RCV005246667	SCV005897033	likely pathogenic	Paragangliomas 4	2024-11-27	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: 16317055, 31492822, 28374168]. This variant is expected to disrupt protein structure [Myriad internal data].
Section on Medical Neuroendocrinolgy, National Institutes of Health	RCV000505338	SCV000599519	likely pathogenic	Hereditary pheochromocytoma-paraganglioma		no assertion criteria provided	research