ClinVar Miner

Submissions for variant NM_004168.4(SDHA):c.3G>T (p.Met1Ile)

dbSNP: rs2126522051
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001930243 SCV002178238 pathogenic Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5 2021-04-28 criteria provided, single submitter clinical testing 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. Disruption of the initiator methionine has been observed in individual(s) with gastrointestinal stromal tumor, renal cell carcinoma, paraganglioma, pheochromocytoma, and complex II deficiency (PMID: 28384794, 26722403, 10746566, 26334176). This variant is not present in population databases (ExAC no frequency). This sequence change affects the initiator methionine of the SDHA mRNA. The next in-frame methionine is located at codon 114. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV003167128 SCV003866408 pathogenic Hereditary cancer-predisposing syndrome 2023-01-12 criteria provided, single submitter clinical testing The p.M1? pathogenic mutation (also known as c.3G>T) is located in coding exon 1 of the SDHA gene and results from a G to T substitution at nucleotide position 3. This alters the methionine residue at the initiation codon (ATG). This alteration has been observed in at least one individual with a personal and/or family history that is consistent with SDHA-related disease (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.

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