NM_004551.3:c.596G>A
Variant summary
Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PM5PP3_StrongBS1_Supporting
The NM_004551.3(NDUFS3):c.596G>A(p.Arg199Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000459 in 1,613,952 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R199W) has been classified as Likely pathogenic.
Frequency
Consequence
NM_004551.3 missense
Scores
Clinical Significance
Conservation
Publications
- mitochondrial complex I deficiency, nuclear type 8Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
- Leigh syndromeInheritance: AR Classification: MODERATE Submitted by: ClinGen
- Leigh syndrome with leukodystrophyInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- mitochondrial complex I deficiencyInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Uncertain_significance. The variant received 5 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152180Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.0000437 AC: 11AN: 251484 AF XY: 0.0000515 show subpopulations
GnomAD4 exome AF: 0.0000499 AC: 73AN: 1461772Hom.: 0 Cov.: 31 AF XY: 0.0000550 AC XY: 40AN XY: 727186 show subpopulations
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152180Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74348 show subpopulations
ClinVar
Submissions by phenotype
Mitochondrial complex I deficiency Uncertain:1
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not provided Uncertain:1
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 199 of the NDUFS3 protein (p.Arg199Gln). This variant is present in population databases (rs771783839, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with NDUFS3-related conditions. ClinVar contains an entry for this variant (Variation ID: 523006). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt NDUFS3 protein function with a positive predictive value of 80%. 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at