Submissions for variant NM_003000.3(SDHB):c.379A>C (p.Ile127Leu)

dbSNP: rs201372280

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000457681	SCV000554007	uncertain significance	Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 127 of the SDHB protein (p.Ile127Leu). This variant is present in population databases (rs201372280, gnomAD 0.0009%). This missense change has been observed in individual(s) with early onset renal cell carcinoma (PMID: 23083876). ClinVar contains an entry for this variant (Variation ID: 412472). 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 not expected to disrupt SDHB protein function with a negative predictive value of 80%. This variant disrupts the p.Ile127 amino acid residue in SDHB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16317055, 16912137, 16916404, 17200167, 19001511, 25683602, 25972245, 29386252, 29951630). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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	RCV000570298	SCV000675062	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-08	criteria provided, single submitter	clinical testing	The p.I127L variant (also known as c.379A>C), located in coding exon 4 of the SDHB gene, results from an A to C substitution at nucleotide position 379. The isoleucine at codon 127 is replaced by leucine, an amino acid with highly similar properties. In one study, this variant was detected in an individual with kidney cancer at 28 years of age; however, it was also detected in the proband's unaffected mother and two unaffected maternal aunts (Ricketts CJ et al. J. Urol. 2012 Dec;188:2063-71). 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.
GeneDx	RCV001755710	SCV002007360	uncertain significance	not provided	2023-09-19	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast or renal cancer, but also in unaffected family members, in published literature (Ricketts et al., 2012; Mittal et al., 2022); This variant is associated with the following publications: (PMID: 34703596, 25972245, 25683602, 16916404, 17200167, 19001511, 29951630, 16912137, 16317055, 29386252, 36200007, 23083876)
Fulgent Genetics, Fulgent Genetics	RCV002481485	SCV002792399	uncertain significance	Gastrointestinal stromal tumor; Carney-Stratakis syndrome; Paragangliomas 4; Pheochromocytoma; Mitochondrial complex 2 deficiency, nuclear type 4	2022-02-14	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003476135	SCV004203008	uncertain significance	Gastrointestinal stromal tumor	2023-06-26	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001755710	SCV004703431	uncertain significance	not provided	2024-01-01	criteria provided, single submitter	clinical testing	SDHB: PM2, PM5