Submissions for variant NM_004168.4(SDHA):c.1A>G (p.Met1Val)

gnomAD frequency: 0.00013  dbSNP: rs1061517

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000230468	SCV000288128	pathogenic	Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5	2025-01-22	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 present in population databases (rs1061517, gnomAD 0.02%). Disruption of the initiator codon has been observed in individuals with autosomal dominant gastrointestinal stromal tumor syndrome, autosomal dominant paraganglioma-pheochromocytoma syndrome (PMID: 26722403, 28384794, 29625052, 30068732), and/or autosomal recessive mitochondrial complex II deficiency (PMID: 10746566, 26334176). ClinVar contains an entry for this variant (Variation ID: 239661). 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	RCV000567727	SCV000674973	pathogenic	Hereditary cancer-predisposing syndrome	2022-08-24	criteria provided, single submitter	clinical testing	The p.M1? pathogenic mutation (also known as c.1A>G), located in coding exon 1 of the SDHA gene, results from an A to G substitution at nucleotide position 1. 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. This alteration has been reported in at least one individual with Leigh syndrome (Baskovich B et al. Genet. Med. 2016 05;18:522-8). A different variant altering the methionine residue (c.1A>C) has been observed in an individual with Leigh syndrome who also carried a functionally deleterious SDHA alteration in trans, as well as in individuals with paraganglioma and gastrointestinal stromal tumor (GIST) (Parfait B et al. Hum. Genet. 2000 Feb;106:236-43; Bausch B et al. JAMA Oncol. 2017 Sep;3(9):1204-1212; Carrera S et al. Hered. Cancer Clin. Pract. 2019 Aug;17:23). 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.
GeneDx	RCV000579224	SCV000680795	pathogenic	not provided	2022-01-04	criteria provided, single submitter	clinical testing	Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 26334176, 30877234, 31665838, 29625052, 32971818, 32676327, 30068732, 33077847, Davidoff2021[Case Report])
Department of Pediatrics, Memorial Sloan Kettering Cancer Center	RCV000656497	SCV000778380	pathogenic	Paragangliomas 5	2018-06-06	criteria provided, single submitter	clinical testing	This mutation was detected in a patient with bladder cancer in our cohort. While this genomic alteration meets ACMG criteria as pathogenic, additional features suggest this variant was driving the bladder cancer in the patient it was detected are lacking. A second hit was not observed in SDHA in the tumor and SDHA/B staining were retained in the tumor sample.
Illumina Laboratory Services, Illumina	RCV000656497	SCV001786669	likely pathogenic	Paragangliomas 5	2022-06-15	criteria provided, single submitter	clinical testing	The SDHA c.1A>G (p.Met1?) variant alters the initiator methionine amino acid and the resultant protein is described as p.Met1? to denote that whether the loss of the methionine at codon 1 prevents all protein translation or causes abnormal protein formation from an alternate methionine is unknown. This variant has been reported in a heterozygous state in an individual with pheochromocytoma (Davidoff et al. 2021) as well as individuals with bladder cancer (Dubart Gault et al. 2018; Carlo et al. 2020) and melanoma (Huang et al. 2018; Aoude et al. 2020). It has also been identified as a somatic variant in a tumor sample from an individual with a carotid paraganglioma (Snezhkina et al. 2020). In addition, the c.1A>G variant was identified in at least two individuals with an autosomal recessive mitochondrial disorder (Baskovich et al. 2016; Han et al. 2019; Yang et al. 2022). Different nucleotide changes that also disrupt the initiation codon, c.1A>C, c.1A>T, c.2T>C, c.2T>G, and c.3G>C, have been reported in individuals with adrenal paraganglioma, carotid paraganglioma, gastrointestinal stromal tumors, or autosomal recessive Leigh syndrome (Parfait et al. 2000; Jiang et al. 2015; Bausch et al. 2017; Carrera et al. 2019). The c.1A>G variant is reported in the Genome Aggregation Database in three alleles at a frequency of 0.000044 in the European (non-Finnish) population (version 3.1.2). Mutagenesis studies using breast cancer cell lines expressing c.1A>G variant and wild-type cDNA showed decreased protein levels and increased accumulation of metabolites in the presence of the variant. The succinate to fumarate ratio was not significantly different from wild-type in the cell lines expressing the variant (Dubart Gault et al. 2018), but a sample from the resected pheochromocytoma from the individual with a germline c.1A>G variant did show an increased succinate to fumarate ratio as well as absent immunohistochemical staining for succinate dehydrogenase subunits A and B (Davidoff et al. 2021). Based on the available evidence, the c.1A>G (p.Met1?) variant is classified as likely pathogenic for hereditary paraganglioma-pheochromocytoma syndrome.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000579224	SCV002009959	likely pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000656497	SCV004933589	pathogenic	Paragangliomas 5	2024-02-06	criteria provided, single submitter	clinical testing	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].
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000656497	SCV005400337	pathogenic	Paragangliomas 5	2023-12-21	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with SDHA-related disorders (MIM#613642, MIM#252011, MIM#619259, MIM#614165) . (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance. Variants in this gene are known to have reduced penetrance for paragangliomas 5 (PMID: 29978154). (I) 0206 - Variant is predicted to result in a loss of the canonical translation initiation codon (ATG). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2 and v3: 16 heterozygotes, 0 homozygotes). (SP) 0311 - Multiple alternative nucleotide changes at the same initiation codon have been observed in gnomAD (v3) (highest allele count: 2 heterozygotes, 0 homozygotes). (I) 0701 - Other canonical translation initiation codon variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Seven variants affecting the canonical translation initiation codon have been observed in heterozygous or compound heterozygous states in multiple individuals with paragangliomas 5 (MIM#614165) and mitochondrial respiratory chain complex II deficiency (MIM#252011) respectively (ClinVar, PMIDs: 10746566, 26722403, 31413764). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times in association with paragangliomas. In addition, it has also been reported in a compound heterozygous state in an individual with Leigh syndrome (ClinVar, PMID: 35014173). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign