ClinVar Genomic variation as it relates to human health

The p.P54S variant (also known as c.160C>T), located in coding exon 3 of the SDHC gene, results from a C to T substitution at nucleotide position 160. The proline at codon 54 is replaced by serine, an amino acid with similar properties. This variant has been identified in an individual with recurrent paragangliomas and gastrointestinal stromal tumor (Ambry internal data). Another alteration at the same codon, p.P54T (c.160C>A), has been detected in multiple individuals with paragangliomas (Ambry internal data). Based on internal structural analysis, P54S destabilizes the SDHC-SDHB interface to a higher degree than a nearby pathogenic variant (Zhou Q et al. Protein Cell, 2011 Jul;2:531-42; Inaoka DK et al. Int J Mol Sci, 2015 Jul;16:15287-308). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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. This variant disrupts the p.Pro54 amino acid residue in SDHC. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae; external communication). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 1776361). This variant has not been reported in the literature in individuals affected with SDHC-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 54 of the SDHC protein (p.Pro54Ser).

This missense variant replaces proline with serine at codon 54 of the SDHC protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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.