ClinVar Miner

Submissions for variant NM_003002.4(SDHD):c.205G>A (p.Glu69Lys) (rs202198133)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000484125 SCV000568557 likely pathogenic not provided 2017-03-06 criteria provided, single submitter clinical testing The E69K variant in the SDHD gene has been reported previously in an individual with biochemical evidence of a severe isolated complex II deficiency, who presented with early progressive encephalomyopathy and was compound heterozygous for the E69K variant and another variant (Jackson et al., 2014). The E69K variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The E69K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. Functional studies showed the complex II assembly and normal function was not restored in patient fibroblasts by expression of E69K mutant cDNA compared to wild type (Jackson et al., 2014). The E69K variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Invitae RCV000696706 SCV000825280 uncertain significance Carney-Stratakis syndrome; Pheochromocytoma; Paragangliomas 1; Cowden syndrome 3 2018-05-29 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 69 of the SDHD protein (p.Glu69Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with encephalomyopathy and isolated mitochondrial complex II deficiency (PMID: 24367056). ClinVar contains an entry for this variant (Variation ID: 156153). Experimental studies have suggested that this variant impairs the normal function of SDHD protein and results in a complex II assembly defect (PMID: 24367056). 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.
OMIM RCV000144171 SCV000189248 pathogenic Mitochondrial complex II deficiency 2014-03-01 no assertion criteria provided literature only

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