Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV002044863 | SCV002108217 | uncertain significance | Gastrointestinal stromal tumor; Paragangliomas 3 | 2022-11-01 | criteria provided, single submitter | clinical testing | Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with altered splicing resulting in an unknown protein product impact (Invitae). 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 1351620). This variant has been observed in individual(s) with paraganglioma-pheochromocytoma syndromes (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects codon 7 of the SDHC mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the SDHC protein. This variant also falls at the last nucleotide of exon 1, which is part of the consensus splice site for this exon. |
| Ambry Genetics | RCV004656677 | SCV005161242 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2024-05-10 | criteria provided, single submitter | clinical testing | The c.20G>A variant (also known as p.R7K), located in coding exon 1 of the SDHC gene, results from a G to A substitution at nucleotide position 20. The amino acid change results in arginine to lysine at codon 7, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 1, which makes it likely to have some effect on normal mRNA splicing. This variant was reported in an individual with features consistent with SDHC-related paraganglioma-pheochromocytoma syndrome (Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. This amino acid position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). In addition, as a missense, this alteration is also predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |