Submissions for variant NM_003001.5(SDHC):c.13T>A (p.Leu5Met)

dbSNP: rs894925936

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000821325	SCV000962079	uncertain significance	Gastrointestinal stromal tumor; Paragangliomas 3	2024-12-04	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 5 of the SDHC protein (p.Leu5Met). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SDHC-related conditions. ClinVar contains an entry for this variant (Variation ID: 663454). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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	RCV001011373	SCV001171683	uncertain significance	Hereditary cancer-predisposing syndrome	2025-02-08	criteria provided, single submitter	clinical testing	The p.L5M variant (also known as c.13T>A), located in coding exon 1 of the SDHC gene, results from a T to A substitution at nucleotide position 13. The leucine at codon 5 is replaced by methionine, 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284704	SCV001470639	uncertain significance	not provided	2024-05-31	criteria provided, single submitter	clinical testing	The SDHC c.13T>A (p.Leu5Met) variant has not been reported in individuals with SDHC-related conditions in the published literature. It also has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
GeneDx	RCV001284704	SCV004031619	uncertain significance	not provided	2024-02-11	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; Has not been previously published as pathogenic or benign to our knowledge
Baylor Genetics	RCV003473514	SCV004203061	uncertain significance	Gastrointestinal stromal tumor	2023-09-13	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004803273	SCV005424080	uncertain significance	Hereditary pheochromocytoma-paraganglioma	2024-02-22	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with methionine at codon 5 of the SDHC protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with SDHC-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.