ClinVar Miner

Submissions for variant NM_005006.7(NDUFS1):c.683T>C (p.Val228Ala) (rs370411488)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000493658 SCV000582622 likely pathogenic not provided 2017-06-05 criteria provided, single submitter clinical testing The V228A variant in the NDUFS1 gene has been reported previously in two affected individuals with isolated complex I deficiency who were compound heterozygous for the V228A variant and a different missense variant on the other allele (Pagniez-Mammeri et al., 2009; Danhauser et al., 2011). Fibroblasts from the two patients showed a significant decrease of complex I activity and strongly reduced amount of NDUFS1 protein levels; expression of wild-type cDNA doubled complex I activity and increased protein levels. Additionally, a significant increase of complex I activity relative to protein level, as well as relative to citrate synthase and complex IV levels, was noted providing supportive data that the variants in NDUFS1 in these two individuals were affecting gene function (Danhauser et al., 2011). The V228A variant was not observed at any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The V228A variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The V228A variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Illumina Clinical Services Laboratory,Illumina RCV000779296 SCV000915878 pathogenic Mitochondrial complex 1 deficiency, nuclear type 5 2017-09-11 criteria provided, single submitter clinical testing The NDUFS1 c.683T>C (p.Val228Ala) variant has been reported in four studies and identified in four compound heterozygotes with complex I deficiency (Pagniez-Mammeri et al. 2009; Hoefs et al. 2010; Danhauser et al. 2011). The three individuals identified by Hoefs et al. (2010) and Danhauser et al. (2011) expired before age four. The variant was absent from 100 healthy controls but is reported at a frequency of 0.000349 in European American population of the Exome Sequencing Project. Analysis of cultured skin fibroblasts from patients found that the enzyme activity of complex I was significantly decreased (Hoefs et al. 2010; Danhauser et al. 2011). Danhauser et al. (2011) also transduced and expressed the variant in a construct with wild type protein and the complex I activity doubled in both individuals with the p.Val228Ala variant. Based on the evidence, the p.Val228Ala variant is classified as pathogenic for NDUFS1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

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