Submissions for variant NM_003000.3(SDHB):c.112C>T (p.Arg38Cys)

gnomAD frequency: 0.00006  dbSNP: rs202119350

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000409187	SCV000487960	uncertain significance	Paragangliomas 4	2015-12-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000456572	SCV000554010	uncertain significance	Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 38 of the SDHB protein (p.Arg38Cys). This variant is present in population databases (rs202119350, gnomAD 0.006%). This missense change has been observed in individuals with paraganglioma (PMID: 23660872; Invitae). ClinVar contains an entry for this variant (Variation ID: 371801). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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.
Ambry Genetics	RCV000570971	SCV000675068	uncertain significance	Hereditary cancer-predisposing syndrome	2024-05-07	criteria provided, single submitter	clinical testing	The p.R38C variant (also known as c.112C>T), located in coding exon 2 of the SDHB gene, results from a C to T substitution at nucleotide position 112. The arginine at codon 38 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been previously identified in an individual with metastatic parganglioma (de Cubas AA et al. Endocr. Relat. Cancer. 2013 Aug;20(4):477-93), but was also identified in 2/1358 non-cancer control individuals and in 0/57 cases, in a study looking at cancer predisposition mutations in patients with cutaneous melanoma and a history of at least two additional non-cutaneous melanoma primary cancers (Pritchard AL et al. PLoS One 2018 Apr;13(4):e0194098). 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.
Fulgent Genetics, Fulgent Genetics	RCV000763775	SCV000894677	uncertain significance	Carney-Stratakis syndrome; Paragangliomas 4; Pheochromocytoma	2018-10-31	criteria provided, single submitter	clinical testing
Mendelics	RCV000986267	SCV001135206	uncertain significance	Gastrointestinal stromal tumor	2019-05-28	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000986267	SCV002030195	uncertain significance	Gastrointestinal stromal tumor	2021-04-02	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
GeneDx	RCV000782212	SCV002599785	uncertain significance	not provided	2023-07-21	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with pheochromocytoma or paraganglioma (de Cubas et al., 2013; Parisien-La Salle et al., 2022); This variant is associated with the following publications: (PMID: 34072806, 23660872, 26269449, 29641532, 34750850)
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002465646	SCV002760224	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000409187	SCV004045359	uncertain significance	Paragangliomas 4	2023-04-24	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics	RCV000986267	SCV005056623	uncertain significance	Gastrointestinal stromal tumor	2024-03-10	criteria provided, single submitter	clinical testing
Gharavi Laboratory, Columbia University	RCV000782212	SCV000920698	uncertain significance	not provided	2018-09-16	no assertion criteria provided	research