chr3-119515865-A-G
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4
The NM_016589.4(TIMMDC1):c.597-1340A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000105 in 152,220 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_016589.4 intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000105 AC: 16AN: 152102Hom.: 0 Cov.: 33
GnomAD4 genome AF: 0.000105 AC: 16AN: 152220Hom.: 0 Cov.: 33 AF XY: 0.000107 AC XY: 8AN XY: 74436
ClinVar
Submissions by phenotype
Mitochondrial complex 1 deficiency, nuclear type 31 Pathogenic:3
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The TIMMDC1 c.597-1340A>G variant is a deep intronic variant that has been reported in a homozygous state as c.596+2146A>G in five individuals with mitochondrial complex I deficiency (Kremer et al. 2017). These individuals were from three unrelated families of differing ethnicities. The variant was shown to result in a TIMMDC1 isoform with a new exon insertion in intron 5 that introduces a frameshift and premature stop codon. Patient fibroblasts showed no detectable protein expression and impaired complex I assembly, which could be at least partially restored by expression of wildtype TIMMDC1. In addition to deficient complex I activity in muscle, the affected individuals showed developmental delay, failure to thrive, hypotonia, muscle wasting, dyskinetic movements, cerebellar signs, and peripheral neuropathy. Some individuals showed abnormalities on brain MRI, and one developed acute episodes with abnormal eye movements, myoclonus, and loss of consciousness. The c.597-1340A>G variant is reported at a frequency of 0.000195 in the European (non-Finnish) population of the Genome Aggregation Database in a region of good sequence coverage, indicating it is rare. Based on the collective evidence, the c.597-1340A>G variant is classified as pathogenic for TIMMDC1-related mitochondrial complex I deficiency. -
Variant summary: TIMMDC1 (legacy name C3orf1) c.597-1340A>G is located at a deep intronic position not widely known to affect splicing. 4/4 computational tools predict no significant impact on normal splicing at the canonical splice sites. However, at least one publication reports RNA sequencing studies that this variant results in the insertion of a poison exon that introduces a frameshift leading to a premature stop codon p.Gly199_Thr200ins5* and thus nonsense mediated decay (NMD) of the aberrant transcript in patient cells (example, Kramer_2017). The variant allele was found at a frequency of 9.6e-05 in 31386 control chromosomes. c.597-1340A>G has been reported in the literature as c.596 + 2146A >G in homozygous and compound heterozygous genotypes in multiple affected individuals from families affected with Mitochondrial Complex 1 Deficiency, Nuclear Type 31 (example, Kremer_2017, Naber_2021, Kumar_2022). These data indicate that the variant is very likely to be associated with disease. One clinical diagnostic laboratory and the OMIM database have submitted clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as pathogenic citing overlapping but not all inclusive evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic. -
not provided Pathogenic:1
This sequence change falls in intron 5 of the TIMMDC1 gene. It does not directly change the encoded amino acid sequence of the TIMMDC1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs781525096, gnomAD 0.02%). This variant has been observed in individuals with mitochondrial complex I deficiency (PMID: 28604674, 33278652, 35091571). It has also been observed to segregate with disease in related individuals. This variant is also known as c.596+2146A>G. ClinVar contains an entry for this variant (Variation ID: 429020). Studies have shown that this variant results in activation of a cryptic splice site, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 28604674). For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at