Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV002045911 | SCV002302748 | uncertain significance | Gastrointestinal stromal tumor; Paragangliomas 3 | 2023-10-03 | criteria provided, single submitter | clinical testing | This sequence change replaces histidine, which is basic and polar, with asparagine, which is neutral and polar, at codon 8 of the SDHC protein (p.His8Asn). This variant is present in population databases (rs746666691, gnomAD 0.02%). 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: 1513452). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The asparagine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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 | RCV002458994 | SCV002738170 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-01-04 | criteria provided, single submitter | clinical testing | The p.H8N variant (also known as c.22C>A), located in coding exon 2 of the SDHC gene, results from a C to A substitution at nucleotide position 22. The histidine at codon 8 is replaced by asparagine, an amino acid with similar properties. This alteration was identified in 2/1358 non-cancer control individuals and in 0/57 cases, in a study looking at cancer predisposition mutations in patients with cutaneous melanoma and a history of at least two additional non-cutaneous melanoma primary cancers (Pritchard AL et al. PLoS One, 2018 Apr;13:e0194098). 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. |
| Neuberg Centre For Genomic Medicine, |
RCV003339895 | SCV004047603 | uncertain significance | Paragangliomas 3 | criteria provided, single submitter | clinical testing | The missense variant p.H8N in SDHC (NM_003001.5) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.His8Asn variant is novel (not in any individuals) in 1000 Genomes. There is a small physicochemical difference between histidine and asparagine, which is not likely to impact secondary protein structure as these residues share similar properties. In silico tools predict the variant to be tolerated. The residue is conserved across species. The amino acid change p.His8Asn in SDHC is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. |