ClinVar Genomic variation as it relates to human health

Variant summary: SDHC c.98C>T (p.Thr33Met) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 251480 control chromosomes. The observed variant frequency is approximately 330.84 fold of the estimated maximal expected allele frequency for a pathogenic variant in SDHC causing Hereditary Paraganglioma-Pheochromocytoma Syndrome phenotype (1.6e-07), suggesting that the variant may be benign. c.98C>T has been reported in the literature in individuals affected with renal cell carcinoma or an unspecified cancer type, without evidence of causality (e.g. Kim_2018, Yngvadottir_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Paraganglioma-Pheochromocytoma Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30583724, 35441217). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in an individual with bilateral renal cell carcinoma in published literature (PMID: 35441217); This variant is associated with the following publications: (PMID: 35441217)

This missense variant replaces threonine with methionine at codon 33 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 been identified in 14/282888 chromosomes 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.

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 33 of the SDHC protein (p.Thr33Met). This variant is present in population databases (rs148566767, gnomAD 0.01%). 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: 407054). 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.

This missense variant replaces threonine with methionine at codon 33 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 been reported in an individual affected with clear cell renal carcinoma (PMID: 35441217). This variant has been identified in 14/282888 chromosomes 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.

The p.T33M variant (also known as c.98C>T), located in coding exon 3 of the SDHC gene, results from a C to T substitution at nucleotide position 98. The threonine at codon 33 is replaced by methionine, an amino acid with 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.

The SDHC c.98C>T variant is predicted to result in the amino acid substitution p.Thr33Met. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.010% of alleles in individuals of East Asian descent in gnomAD. It is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/407054/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.