Submissions for variant NM_004168.4(SDHA):c.1A>C (p.Met1Leu)

dbSNP: rs1061517

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001233940	SCV001406560	pathogenic	Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5	2023-11-19	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 pheochromocytoma, gastrointestinal stromal tumor, and clinical features of complex II deficiency (PMID: 10746566, 28384794, 31413764). ClinVar contains an entry for this variant (Variation ID: 8744). 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). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002415407	SCV002724198	pathogenic	Hereditary cancer-predisposing syndrome	2020-07-06	criteria provided, single submitter	clinical testing	The p.M1? pathogenic mutation (also known as c.1A>C) is located in coding exon 1 of the SDHA gene and results from an A to C substitution at nucleotide position 1. This alters the methionine residue at the initiation codon. 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 an individual with Leigh syndrome who also carried a functionally deleterious SDHA alteration in trans (Parfait B et al. Hum. Genet. 2000 Feb;106:236-43). This alteration has also been observed individuals with paraganglioma and gastrointestinal stromal tumor (GIST) (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, since sequence variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame, this alteration is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003234897	SCV003933740	pathogenic	Neurodegeneration with ataxia and late-onset optic atrophy	2023-05-03	criteria provided, single submitter	clinical testing	Variant summary: SDHA c.1A>C (p.Met1?) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. The next in-frame Methionine is located at codon 114 in exon 4 of the encoded protein sequence. The variant was absent in 114846 control chromosomes. c.1A>C has been reported in the literature as a compound heterozygous genotype in an individual affected with features of Leigh Syndrome with Succinate dehydrogenase deficiency (example, Parfait_2000) and as a heterozygous genotype in individuals affected with features of extra-adrenal thoracid paraganglioma and/or Gastrointestinal stromal tumors (GISTs) (example, Bausch_2017, Carrera_2019). At least one publication reports experimental evidence evaluating an impact on transcript levels (Parfait_2000). The most pronounced variant effect results in mutant transcript representing only 10% of total Flavoprotein (Fp) transcripts, suggesting a high instability of this transcript. The following publications have been ascertained in the context of this evaluation (PMID: 28384794, 31413764, 10746566). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Genetics, Inc.	RCV003450622	SCV004189809	pathogenic	Paragangliomas 5	2023-08-10	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: 28384794, 35014173, 10746566, 32971818].
OMIM	RCV000009283	SCV000029501	pathogenic	Mitochondrial complex II deficiency, nuclear type 1	2000-02-01	no assertion criteria provided	literature only