Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000492968 | SCV000582621 | likely pathogenic | not provided | 2022-11-20 | criteria provided, single submitter | clinical testing | Observed in an apparent homozygous state in a patients with complex I deficiency/Leigh syndrome in the literature (Hoefs et al., 2010; Tuppen et al., 2010); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22820119, 22664328, 31589614, 30055843, 20382551, 20819849, 22142868, 36042640) |
Invitae | RCV000492968 | SCV002273845 | likely pathogenic | not provided | 2022-11-29 | criteria provided, single submitter | clinical testing | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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 NDUFS1 protein function. ClinVar contains an entry for this variant (Variation ID: 50924). This missense change has been observed in individuals with mitochondrial complex I deficiency (PMID: 20382551, 20819849). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs149271416, gnomAD 0.004%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 408 of the NDUFS1 protein (p.Arg408Cys). |
Prevention |
RCV003430654 | SCV004118083 | uncertain significance | NDUFS1-related condition | 2022-08-30 | criteria provided, single submitter | clinical testing | The NDUFS1 c.1222C>T variant is predicted to result in the amino acid substitution p.Arg408Cys. This variant has been reported in the homozygous state in individuals with mitochondrial complex 1 deficiency (Hoefs et al. 2010. PubMed ID: 20382551; Tuppen et al. 2010. PubMed ID: 20819849). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-207006705-G-A). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. |
OMIM | RCV000043636 | SCV000071661 | pathogenic | Mitochondrial complex 1 deficiency, nuclear type 5 | 2010-07-01 | no assertion criteria provided | literature only |