ClinVar Miner

Submissions for variant NM_004168.4(SDHA):c.1769_1770GC[4] (p.His592fs) (rs1561010948)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000691877 SCV000819673 uncertain significance Mitochondrial complex II deficiency; Paragangliomas 5 2018-03-26 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the SDHA gene (p.His592Argfs*54). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 73 amino acids of the SDHA protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SDHA-related disease. This truncation is expected to disrupt the C-terminal domain (residues 586-664) of the SDHA protein (PMID: 21858060), which is structurally required for flavinylation and binding with its cofactors (PMID: 23043141, 25488574). Experimental studies using a yeast model have shown that mutant strains with disruption of the C-terminal region affect heme binding, SDH complex assembly, and interaction with other subunits such as SDHB and SDHAF2 (PMID: 23043141). However, the clinical significance of these results is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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