Submissions for variant NM_003001.5(SDHC):c.473T>C (p.Leu158Pro)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetics and Molecular Pathology, SA Pathology	RCV002466815	SCV002761521	uncertain significance	Paragangliomas 3	2022-01-10	criteria provided, single submitter	clinical testing	The heterozygous variant c.473T>C detected in exon 6 of the SDHC gene is a missense change resulting in an amino acid substitution from a Leucine to a Proline at codon 158, p.(Leu158Pro). This variant occurs at a moderately conserved amino acid within the Succinate dehydrogenase/Fumarate reductase transmembrane subunit domain. This variant is recorded 3 times in the LOVD database as of uncertain significance, but has not been reported in ClinVar. This variant was identified in individuals with paraganglioma (Burnichon et al, J Clin Endocrinol Metab (2009) 94(8):2817-27 and Bauters et al, J Med Genet (2003) 40(6): e75). No other missense changes at this codon are recorded in ClinVar. This variant has not been observed in population database (gnomAD). In silico protein prediction programs (REVEL, AGVGD, SIFT and PolyPhen2) are inconsistent regarding the effect of this variant on protein structure and function. Based on current knowledge, this is a variant of uncertain significance (Class 3) and predictive testing is not available.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002571402	SCV003523976	uncertain significance	Gastrointestinal stromal tumor; Paragangliomas 3	2022-10-01	criteria provided, single submitter	clinical testing	This missense change has been observed in individual(s) with paraganglioma (PMID: 12807974, 30877234). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 158 of the SDHC protein (p.Leu158Pro). 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. 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 SDHC protein function.
Revvity Omics, Revvity	RCV003491117	SCV004237194	uncertain significance	not provided	2023-03-08	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV003491117	SCV005198199	uncertain significance	not provided	2023-08-16	criteria provided, single submitter	clinical testing