ClinVar Genomic variation as it relates to human health

This variant is considered pathogenic. This variant is located within the gene translation start codon (p.Met1?) and is predicted to result in abnormal protein translation. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 35014173, 28384794, 10746566, 26722403, 32971818].

This sequence change affects the initiator methionine of the SDHA mRNA. The next in-frame methionine is located at codon 114. This variant is present in population databases (rs750380279, gnomAD 0.006%). Disruption of the initiator codon has been observed in individuals with gastrointestinal stromal tumor, renal cell carcinoma, paraganglioma, pheochromocytoma, and complex II deficiency (PMID: 10746566, 26334176, 26722403, 28384794). ClinVar contains an entry for this variant (Variation ID: 582115). 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). Rescue of translational initiation by the downstream methionine would be expected to result in the disruption of the N-terminal part of the SDHA protein, which is important for FAD binding (PMID: 25488574, 15989954). This suggests that disruption of this region of the protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.

The p.M1? pathogenic mutation (also known as c.2T>A) is located in coding exon 1 of the SDHA gene and results from a T to A substitution at nucleotide position 2. This alters the methionine residue at the initiation codon (ATG). There is an in-frame methionine 114 amino acids downstream from this initiation site which may result in an N-terminal truncation; however, direct evidence is unavailable. Other alterations impacting the initiation codon (c.2T>C, c.2T>G, c.1A>C, c.1A>G) have been reported in individuals with personal history consistent with hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes, including gastrointestinal stromal tumor (GIST), renal cell carcinoma, and carotid paraganglioma (Jiang Q et al. Int J Clin Exp Pathol 2015 Oct;8(10):12188-97; Bausch B et al. JAMA Oncol, 2017 Sep;3:1204-1212; Carrera S et al. Hered. Cancer Clin. Pract. 2019 Aug;17:23). Further, the c.1A>C alteration impacting the SDHA initiation codon has been observed in an individual with autosomal recessive Leigh syndrome who also carried a functionally deleterious SDHA alteration in trans (Parfait B et al. Hum. Genet. 2000 Feb;106:236-43). 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.