Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV001015411 | SCV001176239 | uncertain significance | Hereditary cancer-predisposing syndrome | 2019-03-06 | criteria provided, single submitter | clinical testing | The p.S8* variant (also known as c.23C>A), located in coding exon 1 of the SDHAF2 gene, results from a C to A substitution at nucleotide position 23. This changes the amino acid from a serine to a stop codon within coding exon 1. Premature stop codons are typically deleterious in nature; however, there is an alternate in-frame methionine 12 amino acids from the initiation site, and the significance of the N-terminus for this protein is not well established. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Labcorp Genetics |
RCV002549418 | SCV003277084 | pathogenic | Hereditary pheochromocytoma-paraganglioma | 2023-03-20 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 821217). This variant has not been reported in the literature in individuals affected with SDHAF2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser8*) in the SDHAF2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SDHAF2 are known to be pathogenic (PMID: 22241717, 26096992). |
| All of Us Research Program, |
RCV002549418 | SCV004839124 | likely pathogenic | Hereditary pheochromocytoma-paraganglioma | 2024-01-08 | criteria provided, single submitter | clinical testing | This variant changes 1 nucleotide in exon 1 of the SDHAF2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. However, an alternate in-frame methionine is present at codon 13 and may contribute to translational rescue of this variant, although this has not been demonstrated experimentally. Amino acid residues 1-36 encode the mitochondrial presequence import signal (PMID: 24414418), and the loss of the first 12 amino acids therefore may impact mitochondrial import function. To our knowledge, this variant has not been reported in individuals affected with SDHAF2-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. |