Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000478025 | SCV000571847 | pathogenic | not provided | 2023-06-01 | criteria provided, single submitter | clinical testing | Initiation codon variant in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26722403, 25488574, 10746566, 15989954, 21858060, 33372952, 28384794) |
Invitae | RCV000649438 | SCV000771266 | pathogenic | Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5 | 2023-11-28 | criteria provided, single submitter | clinical testing | This sequence change affects the initiator methionine of the SDHA mRNA. The next in-frame methionine is located at codon 114. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individuals with complex II deficiency, gastrointestinal stromal tumor and renal cell carcinoma, and/or paraganglioma (PMID: 10746566, 26722403, 28384794). ClinVar contains an entry for this variant (Variation ID: 422382). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of the initiator codon affects SDHA function (PMID: 10746566). This variant disrupts the N-terminal part of the SDHA protein, which is important for FAD binding (PMID: 25488574, 15989954, 21858060). While functional studies have not been performed to directly test the effect of this variant on SDHA protein function, this suggests that disruption of this region of the protein is causative of disease. For these reasons, this variant has been classified as Pathogenic. |
Ambry Genetics | RCV002438178 | SCV002748830 | pathogenic | Hereditary cancer-predisposing syndrome | 2020-08-06 | criteria provided, single submitter | clinical testing | The p.M1? pathogenic mutation (also known as c.2T>G) is located in coding exon 1 of the SDHA gene and results from a T to G substitution at nucleotide position 2. This alters the methionine residue at the initiation codon (ATG). This alteration has been reported in an individual diagnosed with a carotid paraganglioma at age 27, who had no family history of paraganglioma or pheochromocytoma (Bausch B et al. JAMA Oncol, 2017 Sep;3:1204-1212). In addition to the clinical data presented in the literature, sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
Fulgent Genetics, |
RCV002506172 | SCV002808756 | likely pathogenic | Mitochondrial complex II deficiency, nuclear type 1; Dilated cardiomyopathy 1GG; Paragangliomas 5; Neurodegeneration with ataxia and late-onset optic atrophy | 2022-04-27 | criteria provided, single submitter | clinical testing | |
Human Genome Sequencing Center Clinical Lab, |
RCV001257552 | SCV001434378 | pathogenic | Rhabdomyosarcoma | 2020-09-01 | no assertion criteria provided | provider interpretation |