ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.26200G>A (p.Ala8734Thr)

gnomAD frequency: 0.00002  dbSNP: rs727503646
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000152394 SCV000201373 uncertain significance not specified 2013-08-14 criteria provided, single submitter clinical testing The Ala7490Thr variant in TTN has not been reported in individuals with cardiomy opathy or in large population studies. Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that thi s amino acid change may not impact the protein, though this information is not p redictive enough to rule out pathogenicity. This variant is located in the last base of the exon, which is part of the 5' splice region. Computational tools do suggest an impact to splicing, though this information is not predictive enough to determine pathogenicity. Additional information is needed to fully assess the clinical significance of this variant.
Eurofins Ntd Llc (ga) RCV000725609 SCV000338114 uncertain significance not provided 2016-05-18 criteria provided, single submitter clinical testing
Invitae RCV001850078 SCV002283596 uncertain significance Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2022-10-05 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 8734 of the TTN protein (p.Ala8734Thr). This variant also falls at the last nucleotide of exon 90, which is part of the consensus splice site for this exon. This variant is present in population databases (rs727503646, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with TTN-related conditions. ClinVar contains an entry for this variant (Variation ID: 166149). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant is located in the I band of TTN (PMID: 25589632). Variants in this region may be clinically relevant, but have not been definitively shown to cause cardiomyopathy or neuromuscular disease (PMID: 27493940, 32778822). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics RCV002483319 SCV002779793 uncertain significance Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J; Tibial muscular dystrophy; Myopathy, myofibrillar, 9, with early respiratory failure; Early-onset myopathy with fatal cardiomyopathy; Hypertrophic cardiomyopathy 9 2021-09-18 criteria provided, single submitter clinical testing

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