ClinVar Miner

Submissions for variant NM_004550.4(NDUFS2):c.875T>C (p.Met292Thr) (rs150667550)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000198967 SCV000251875 uncertain significance not provided 2018-11-26 criteria provided, single submitter clinical testing The M292T variant has previously been reported in association with Leigh syndrome due to mitochondrial complex I deficiency in four unrelated individuals who were also compound heterozygous for other variants in the NDUFS2 gene, however functional studies were not performed for any of these variants (Tuppen et al, 2010). The M292T 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. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether the M292T variant is a pathogenic variant or a rare benign variant.
Illumina Clinical Services Laboratory,Illumina RCV000778944 SCV000915364 likely pathogenic Mitochondrial complex I deficiency 2018-11-26 criteria provided, single submitter clinical testing The NDUFS2 c.875T>C (p.Met292Thr) missense variant has been reported in at least two studies in which it is found in a compound heterozygous state in a total of five individuals with mitochondrial complex I deficiency (Tuppen et al. 2010; DaRe et al. 2013). Control data are unavailable for this variant, which is reported at a frequency of 0.004013 in the Other population of the Genome Aggregation Database. Complex I activity assays and protein expression levels were performed on cultured skin fibroblasts from three probands with decreased complex I activity and reduced NDUFA9 and NDUFA8 protein levels found in fibroblasts from two of the probands and complex I activity comparable to controls and significantly increased expression of NDUFA9 and NDUFB8 in the third, which was attributed to a compensatory cellular response to the variant NDUFS2 (Tuppen et al. 2010). Based on the evidence, the p.Met292Thr variant is classified as likely pathogenic for mitochondrial respiratory chain complex I deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

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