ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.4645+8G>T

gnomAD frequency: 0.00029  dbSNP: rs144456585
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000176695 SCV000228392 likely benign not specified 2015-02-06 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000176695 SCV000271037 likely benign not specified 2015-07-09 criteria provided, single submitter clinical testing c.4645+8G>T in Intron 26 of TTN: This variant is not expected to have clinical s ignificance because it is not located within the splice consensus sequence. It h as been identified in 0.15% (14/9232) of African chromosomes by the Exome Aggreg ation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs144456585).
Invitae RCV000550606 SCV000643218 benign Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2024-01-30 criteria provided, single submitter clinical testing
GeneDx RCV000176695 SCV000722246 likely benign not specified 2018-02-20 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Genome-Nilou Lab RCV001840251 SCV002101496 benign Autosomal recessive limb-girdle muscular dystrophy type 2J 2021-09-10 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV001840252 SCV002101497 benign Myopathy, myofibrillar, 9, with early respiratory failure 2021-09-10 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV001840253 SCV002101498 benign Early-onset myopathy with fatal cardiomyopathy 2021-09-10 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV001840250 SCV002101499 benign Tibial muscular dystrophy 2021-09-10 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000176695 SCV004020346 benign not specified 2023-06-12 criteria provided, single submitter clinical testing Variant summary: TTN c.4645+8G>T alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 9.3e-05 in 247318 control chromosomes, predominantly at a frequency of 0.0013 within the African or African-American subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.4645+8G>T in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Clinical Genetics, Academic Medical Center RCV000176695 SCV001920869 benign not specified no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV001726021 SCV001964724 likely benign not provided no assertion criteria provided clinical testing

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