ClinVar Miner

Submissions for variant NM_024120.5(NDUFAF5):c.749G>T (p.Gly250Val) (rs757043077)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000431261 SCV000515883 likely pathogenic not provided 2017-05-19 criteria provided, single submitter clinical testing The G250V variant in the NDUFAF5 gene has been previously reported as a founder mutation in the Ashkenazi Jewish population associated with combined mitochondrial complex I and IV deficiency (Saada et al., 2012). This variant was not observed 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 G250V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. The G250V variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Invitae RCV000431261 SCV001226001 pathogenic not provided 2019-10-02 criteria provided, single submitter clinical testing This sequence change replaces glycine with valine at codon 250 of the NDUFAF5 protein (p.Gly250Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine. This variant is present in population databases (rs757043077, ExAC 0.008%). This variant has been observed to segregate with mitochondrial complex I deficiency in families (PMID: 21607760). ClinVar contains an entry for this variant (Variation ID: 372253). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000412492 SCV000490328 pathogenic Mitochondrial complex 1 deficiency, nuclear type 16 2018-12-13 no assertion criteria provided literature only
Division of Human Genetics,Children's Hospital of Philadelphia RCV000477759 SCV000536831 likely pathogenic Mitochondrial complex I deficiency 2016-01-15 no assertion criteria provided research

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