ClinVar Miner

Submissions for variant NM_007103.4(NDUFV1):c.365C>T (p.Pro122Leu)

gnomAD frequency: 0.00002  dbSNP: rs750831299
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000197256 SCV000251937 likely pathogenic not provided 2021-02-06 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25017538, 23596069, 23623855, 25615419, 31292494, 30770271, 30055843, 32445240, 32342562)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780530 SCV000917866 likely pathogenic not specified 2018-10-15 criteria provided, single submitter clinical testing Variant summary: NDUFV1 c.365C>T (p.Pro122Leu) results in a non-conservative amino acid change located in the NADH-ubiquinone oxidoreductase 51kDa subunit, FMN-binding domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.9e-05 in 245506 control chromosomes (gnomAD). c.365C>T has been reported in the literature in individuals affected with Leigh Syndrome (Bjorkman_2015, Lieber_2013). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV000197256 SCV002248893 pathogenic not provided 2022-08-23 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NDUFV1 protein function. ClinVar contains an entry for this variant (Variation ID: 214852). This missense change has been observed in individuals with mitochondrial complex I deficiency or Leigh syndrome (PMID: 23596069, 25615419, 32445240). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs750831299, gnomAD 0.006%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 122 of the NDUFV1 protein (p.Pro122Leu).

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