Submissions for variant NM_007103.4(NDUFV1):c.1156C>T (p.Arg386Cys)

gnomAD frequency: 0.00001  dbSNP: rs150966634

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000482108	SCV000566902	pathogenic	not provided	2024-08-08	criteria provided, single submitter	clinical testing	Has been reported previously in individuals with mitochondrial complex I deficiency who were homozygous for R386C, or were compound heterozygous R386C with another NDUFV1 variant, in published literature and patients referred for genetic testing at GeneDx (PMID: 23562761, 19073330, 26684010); Published functional studies demonstrate a damaging effect: the R386C variant results in an impaired complex I activity with decreased flavin mononucleotide (FMN) content (PMID: 26345448); Not observed at significant frequency in large population cohorts (gnomAD); 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: 26684010, 27126960, 28441825, 33182419, 23266820, 19073330, 23562761, 26024641, 29272804, 29353736, 29948731, 30777920, 29976978, 32180488, 32005694, 34302356, 35803560, 36801247, 26345448)
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001004858	SCV001164336	likely pathogenic	Mitochondrial complex I deficiency, nuclear type 1	2018-12-03	criteria provided, single submitter	research	The homozygous p.Arg386Cys variant in NDUFV1 was identified by our study in 6 individuals with primary microcephaly. This variant has been reported in the literature in the case of one homozygous affected female proband and her affected brother. It has also been seen in two compound heterozygous affected brothers alongside the likely pathogenic c.914-8G_947del mutation (Breningstall et al. 2008, PMID: 19073330; Ortega-Recalde et al. 2013 PMID: 23562761). A different pathogenic variant, p.Arg386His, has been identified at this amino acid residue, further provding evidence for pathogenicity. This variant has been identified in 0.08% (26/30782) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs150966634). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PP3, PM3, PM5 (Richards 2015).
Bruce Lefroy Centre, Murdoch Childrens Research Institute	RCV001662464	SCV001879330	likely pathogenic	Mitochondrial complex 1 deficiency, nuclear type 4		criteria provided, single submitter	research
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV001662464	SCV001976533	pathogenic	Mitochondrial complex 1 deficiency, nuclear type 4		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000482108	SCV002133943	pathogenic	not provided	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 386 of the NDUFV1 protein (p.Arg386Cys). This variant is present in population databases (rs150966634, gnomAD 0.08%). This missense change has been observed in individual(s) with mitochondrial complex I deficiency (PMID: 26024641, 32180488, 33182419). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 419230). 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 with a positive predictive value of 80%. Studies have shown that this missense change alters NDUFV1 gene expression (PMID: 33182419). This variant disrupts the p.Arg386 amino acid residue in NDUFV1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20818383, 26345448). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001662464	SCV002768369	pathogenic	Mitochondrial complex 1 deficiency, nuclear type 4	2020-05-21	criteria provided, single submitter	clinical testing	A homozygous missense variant was identified, NM_007103.3(NDUFV1):c.1156C>T in exon 8 of 10 of the NDUFV1 gene. This substitution is predicted to create a major amino acid change from arginine to cysteine at position 386 of the protein, NP_009034.2(NDUFV1):p.(Arg386Cys). The arginine at this position has high conservation (100 vertebrates, UCSC), and is located within the NADH-ubiquinone oxidoreductase-F iron-sulfur binding region (PDB). In silico software predicts this variant to be damaging (PolyPhen, SIFT, CADD, MutationTaster). The variant is present in the gnomAD population database at a global allele frequency of 0.01% (31 heterozygotes; 0 homozygotes), and is enriched in the South Asian population at a frequency of 0.09%. An alternative change to histidine at the same residue has also been reported in the gnomAD database at a frequency of 0.005%. The variant has previously been reported as pathogenic in patients with mitochondrial complex I deficiency and has been shown to segregate with the disease in families (ClinVar, Breningstall, G. et al. (2008), Srivastava, A. et al. (2018), Ortega-Recalde, O. et al. (2013), Marin, S. et al. (2013)). A different variant in the same codon resulting in a change to histidine has also been shown to cause mitochondrial complex I deficiency (ClinVar, Vilain, C. et al. (2012)). Based on information available at the time of curation, this variant has been classified as PATHOGENIC.
Neuberg Centre For Genomic Medicine, NCGM	RCV001662464	SCV002820278	pathogenic	Mitochondrial complex 1 deficiency, nuclear type 4		criteria provided, single submitter	clinical testing	The missense variant p.R386C in NDUFV1 (NM_007103.3) has been previously reported in multiple affected individuals. It is a founder mutation in South Asians (Srivastava A et al, 2018). The missense variant c.1156C>T (p.R386C) in NDUFV1 (NM_007103.4) is observed in 28/30616 (0.0915%) alleles from individuals of South Asian background in the gnomAD dataset (Exome Aggregation Consortium et al., 2016), but was not seen in the homozygous state. It has been classified in the ClinVar database as Likely Pathogenic/Pathogenic. There is a large physicochemical difference between arginine and cysteine, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. The p.R386C missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 386 of NDUFV1 is conserved in all mammalian species. The nucleotide c.1156 in NDUFV1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. As it is a Founder mutation, it has been classified as Pathogenic.
Revvity Omics, Revvity	RCV001662464	SCV003825896	pathogenic	Mitochondrial complex 1 deficiency, nuclear type 4	2023-10-18	criteria provided, single submitter	clinical testing