ClinVar Miner

Submissions for variant NM_016589.4(TIMMDC1):c.597-1340A>G (rs781525096)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000493542 SCV001251571 pathogenic Mitochondrial complex 1 deficiency, nuclear type 31 2020-02-25 criteria provided, single submitter clinical testing 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.
OMIM RCV000493542 SCV000581394 pathogenic Mitochondrial complex 1 deficiency, nuclear type 31 2018-12-13 no assertion criteria provided literature only

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