ClinVar Miner

Submissions for variant NM_018116.4(MSTO1):c.971C>T (p.Thr324Ile)

gnomAD frequency: 0.00004  dbSNP: rs622288
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Undiagnosed Diseases Network, NIH RCV000505816 SCV000746659 likely pathogenic Mitochondrial myopathy-cerebellar ataxia-pigmentary retinopathy syndrome 2017-12-14 criteria provided, single submitter clinical testing The c.971C>T (p.Thr324Ile) variant in MSTO1 is a nonsense variant. This variant was identified as a compound heterozygote with c.676C>T (p.Gln226Ter). The variant is seen in 13 individual in gnomAD as a heterozygote and has been reported in a similarly affected patient.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000505816 SCV001623323 likely pathogenic Mitochondrial myopathy-cerebellar ataxia-pigmentary retinopathy syndrome 2021-04-23 criteria provided, single submitter clinical testing Variant summary: MSTO1 c.971C>T (p.Thr324Ile) results in a non-conservative amino acid change located in the DML1/Misato, tubulin domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 250888 control chromosomes (gnomAD). c.971C>T has been reported in the literature in four independent indviduals carrying a second MSTO1 variant, whose clinical features overlap with Mitochondrial Myopathy-Cerebellar Ataxia-Pigmentary Retinopathy Syndrome, including delayed motor and speech development, muscle weakness, unsteady gait/poor coordination, tremor, and abnormal EMG, MRI and/or muscle biopsy (Nasca_2017, Donkervoort_2019, Jiao_2020, Lee_2020). To our knowledge, no conclusive functional/experimental studies have been performed on the variant of interest. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
GeneDx RCV001788237 SCV002030986 likely pathogenic not provided 2024-06-03 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29339779, 28544275, 31130378, 30684668, 31607746, 31463572, 35598585, 33222031, 35446979, 33672784, 36468072)
3billion RCV000505816 SCV002059089 pathogenic Mitochondrial myopathy-cerebellar ataxia-pigmentary retinopathy syndrome 2022-01-03 criteria provided, single submitter clinical testing Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000438833, PS1_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:28544275, PS3_S). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000043, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India RCV000505816 SCV002499642 likely pathogenic Mitochondrial myopathy-cerebellar ataxia-pigmentary retinopathy syndrome criteria provided, single submitter clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc RCV000505816 SCV005416914 likely pathogenic Mitochondrial myopathy-cerebellar ataxia-pigmentary retinopathy syndrome criteria provided, single submitter clinical testing PM2_Supporting+PS3_Supporting+PM3_Strong+PP4
OMIM RCV000505816 SCV000600007 pathogenic Mitochondrial myopathy-cerebellar ataxia-pigmentary retinopathy syndrome 2017-09-22 no assertion criteria provided literature only
Ambry Genetics RCV001266925 SCV001445106 uncertain significance Inborn genetic diseases 2017-12-18 flagged submission clinical testing

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