ClinVar Miner

Submissions for variant NM_007103.4(NDUFV1):c.349G>A (p.Ala117Thr)

gnomAD frequency: 0.00001  dbSNP: rs757486575
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000200734 SCV000251936 pathogenic not provided 2024-04-26 criteria provided, single submitter clinical testing Identified with a second NDUFV1 variant in a patient with clinical features of primary mitochondrial disorder in published literature (PMID: 32445240, 34052969); Published functional studies demonstrate a damaging effect: disrupt enzyme assembly or stability and result in loss of complex 1 expression (PMID: 26345448); 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: 23631824, 32445240, 26345448, 34052969)
Labcorp Genetics (formerly Invitae), Labcorp RCV000200734 SCV003439834 likely pathogenic not provided 2024-01-09 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 117 of the NDUFV1 protein (p.Ala117Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of mitochondrial complex I deficiency (PMID: 23631824, 32445240). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 214851). 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 not expected to disrupt NDUFV1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects NDUFV1 function (PMID: 26345448). 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.
Revvity Omics, Revvity RCV003137782 SCV003813545 uncertain significance Mitochondrial complex 1 deficiency, nuclear type 4 2020-10-12 flagged submission clinical testing

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