Submissions for variant NM_003000.3(SDHB):c.67C>G (p.Leu23Val)

dbSNP: rs1553179319

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000519644	SCV000621618	uncertain significance	not provided	2020-02-12	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV000633968	SCV000755241	uncertain significance	Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 23 of the SDHB protein (p.Leu23Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SDHB-related conditions. ClinVar contains an entry for this variant (Variation ID: 452783). 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 95%. 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	RCV002367747	SCV002661836	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-14	criteria provided, single submitter	clinical testing	The p.L23V variant (also known as c.67C>G), located in coding exon 1 of the SDHB gene, results from a C to G substitution at nucleotide position 67. The leucine at codon 23 is replaced by valine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Baylor Genetics	RCV003476224	SCV004203012	uncertain significance	Gastrointestinal stromal tumor	2024-03-24	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004003645	SCV004832392	uncertain significance	Hereditary pheochromocytoma-paraganglioma	2023-05-04	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 23 of the SDHB protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with SDHB-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.