ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.45895G>A (p.Glu15299Lys)

gnomAD frequency: 0.00001  dbSNP: rs397517582
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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 RCV000040264 SCV000063955 uncertain significance not specified 2018-08-16 criteria provided, single submitter clinical testing The p.Glu12731Lys variant in TTN has not been previously reported in individual s with cardiomyopathy, but has been identified in 2/110474 of European chromosom es by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs397517582). This variant is located in the last three bases of the exon , which is part of the 5? splice region. While computational tools do not predic t altered splicing, other computational analysis suggest that this variant may i mpact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Glu12731Lys varia nt is uncertain. ACMG/AMP Criteria applied: PM2, PP3.
Athena Diagnostics Inc RCV000714037 SCV000844700 uncertain significance not provided 2017-10-09 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000040264 SCV002014967 uncertain significance not specified 2021-10-18 criteria provided, single submitter clinical testing Variant summary: TTN c.38191G>A (p.Glu12731Lys) results in a conservative amino acid change located in the I-band region of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8.1e-06 in 247536 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.38191G>A has been reported in the literature in an individual affected with hypertrophic cardiomyopathy (Burstein_2021). This report does not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics RCV002408531 SCV002723196 uncertain significance Cardiovascular phenotype 2019-01-23 criteria provided, single submitter clinical testing The c.18700G>A variant (also known as p.E6234K), located in coding exon 74 of the TTN gene, results from a G to A substitution at nucleotide position 18700. This change occurs in the last base pair of coding exon 74, which makes it likely to have some effect on normal mRNA splicing. In addition to potential splicing impact, the amino acid change results in glutamic acid to lysine at codon 6234, an amino acid with similar properties. Both the nucleotide and amino acid positions are highly conserved in available vertebrate species. Using two different splice site prediction tools, this alteration is predicted by ESEfinder to weaken the efficiency of the native splice donor site, but is not predicted to have a deleterious effect on this splice donor site by BDGP; however, direct evidence is unavailable. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.

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