ClinVar Miner

Submissions for variant NM_004168.4(SDHA):c.1272C>G (p.His424Gln) (rs754805626)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000521376 SCV000620634 uncertain significance not provided 2017-09-22 criteria provided, single submitter clinical testing The H424Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The H424Q variant is observed in 11/66564 (0.016%) alleles from individuals of European background in large population cohorts (Lek et al., 2016). The H424Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000477192 SCV000553898 uncertain significance Mitochondrial complex II deficiency; Paragangliomas 5 2018-11-05 criteria provided, single submitter clinical testing This sequence change replaces histidine with glutamine at codon 424 of the SDHA protein (p.His424Gln). The histidine residue is moderately conserved and there is a small physicochemical difference between histidine and glutamine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with SDHA-related disease. ClinVar contains an entry for this variant (Variation ID: 412380). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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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