Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BS1_Supporting
The NM_001377299.1(NDUFS2):c.1212G>A(p.Lys404Lys) variant causes a splice region, synonymous change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000257 in 1,608,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
NDUFS2 (HGNC:7708): (NADH:ubiquinone oxidoreductase core subunit S2) The protein encoded by this gene is a core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (complex I). Mammalian mitochondrial complex I is composed of at least 43 different subunits, 7 of which are encoded by the mitochondrial genome, and the rest are the products of nuclear genes. The iron-sulfur protein fraction of complex I is made up of 7 subunits, including this gene product. Complex I catalyzes the NADH oxidation with concomitant ubiquinone reduction and proton ejection out of the mitochondria. Mutations in this gene are associated with mitochondrial complex I deficiency. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Oct 2009]
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000223 (34/152254) while in subpopulation NFE AF= 0.000412 (28/68024). AF 95% confidence interval is 0.000292. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Uncertain significance, criteria provided, single submitter
clinical testing
GeneDx
Dec 10, 2024
Reported in an individual with drug resistant epilepsy who is also homozygous for a variant in SV2A (PMID: 37985816); In silico analysis indicates that this variant does not alter splicing; This variant is associated with the following publications: (PMID: 37985816) -
Uncertain significance, criteria provided, single submitter
not provided
Breakthrough Genomics, Breakthrough Genomics
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Uncertain significance, criteria provided, single submitter
clinical testing
Labcorp Genetics (formerly Invitae), Labcorp
Jan 06, 2025
This sequence change affects codon 404 of the NDUFS2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the NDUFS2 protein. This variant also falls at the last nucleotide of exon 12, which is part of the consensus splice site for this exon. This variant is present in population databases (rs145959971, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with NDUFS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 214796). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Mitochondrial complex 1 deficiency, nuclear type 6 Uncertain:2
Uncertain significance, criteria provided, single submitter
curation
Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University
Dec 30, 2017
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Uncertain significance, criteria provided, single submitter
clinical testing
Genome-Nilou Lab
Apr 11, 2023
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Mitochondrial complex I deficiency, nuclear type 1 Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Illumina Laboratory Services, Illumina
Apr 27, 2017
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -