ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.34612+1G>A

gnomAD frequency: 0.00001  dbSNP: rs577363824
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000473977 SCV000542748 uncertain significance Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2021-08-24 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000502600 SCV000597697 pathogenic not provided 2016-07-21 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV001256858 SCV001433348 likely pathogenic Dilated cardiomyopathy 1A 2020-03-17 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001824786 SCV002074149 uncertain significance not specified 2022-01-08 criteria provided, single submitter clinical testing Variant summary: TTN c.30709+1G>A (also known as NM_001267550.2:c.34612+1G>A) alters a conserved nucleotide located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 5' splicing donor site located at intron 145. However, these predictions have yet to be confirmed by functional studies. Furthermore, the exon predicted to be impacted by this alteration is not a constitutively expressed exon (low PSI score) and therefore the clinical impact of this splicing alteration is unknown. The variant allele was found at a frequency of 1.6e-05 in 185860 control chromosomes. c.30709+1G>A has not been reported in the literature in individuals affected with Limb-Girdle Muscular Dystrophy, Type 2J/Cardiomyopathy. However, it has been reported in at-least two controls individuals of European ancestery in the UK Biobank (example, Choi_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Limb-Girdle Muscular Dystrophy, Type 2J/Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance.

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