ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.59729C>T (p.Thr19910Ile) (rs369476725)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000154934 SCV000616114 uncertain significance not specified 2017-02-10 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000765564 SCV000896879 uncertain significance Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J; Distal myopathy Markesbery-Griggs type; Hereditary myopathy with early respiratory failure; Myopathy, early-onset, with fatal cardiomyopathy; Familial hypertrophic cardiomyopathy 9 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000786261 SCV000978012 likely benign not provided 2018-04-06 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.
Invitae RCV000643026 SCV000764713 uncertain significance Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2017-08-17 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000154934 SCV000204616 uncertain significance not specified 2017-06-28 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Thr17342Ile v ariant in TTN has previously been identified by our laboratory in one Caucasian individual with DCM, who also carried a likely pathogenic variant sufficient to explain their disease. This variant has also been identified in 0.18% (18/9784) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http ://gnomad.broadinstitute.org; dbSNP rs369476725). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, tho ugh this information is not predictive enough to determine pathogenicity. In sum mary, while the clinical significance of the Thr17342Ile variant is uncertain, i ts frequency suggests that it is more likely to be benign.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000786261 SCV000925012 uncertain significance not provided 2017-10-16 no assertion criteria provided provider interpretation p.Thr17342Ile (c.52025C>T) in exon 251 of the TTN gene (NM_133378.4; Chr2g.179456902G>A). SCICD Classification: variant of uncertain significance, likely benign based on relatively high frequency in the general population, lack of case data and failure to segregate with disease . We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Gene-level evidence: TTN: TTN encodes titin (also known as connectin), the largest protein in humans; titin plays a critical role in the elastic properties of the sarcomere. Two titin molecules span the sarcomere, anchored at the Z-line and M-line. TTN truncating variants are seen in 13-30% of people with DCM and are thought to confer pathogenesis in a dominant-negative fashion (Herman et al 2012, Roberts et al 2015). There is strong evidence implicating them in the pathogenesis of DCM, though it remains unclear whether they are confer risk in a Mendelian or multifactorial fashion (Watkins et al 2015). Furthermore, each individual TTN variant must be evaluated carefully for potential pathogenicity given the presence of truncating TTN variants in 1-3% of the general population (Herman et al 2012, Roberts et al 2015) and the failure of some TTN truncating variants to segregate in DCM families (Norton et al 2013). Case data (not including our patient): ClinVar: present in 1 lab: Laboratory for Molecular Medicine: 1 patient with DCM who had a pathogenic variant in another gene. Cases in the literature: none reported. Segregation data: none reported. Functional data: none reported. In silico data (missense variants only): Per the test report, "Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. " Conservation data: The threonine at codon 17342 is almost completely conserved across species. Neighboring amino acids are similarly conserved. Nearby pathogenic variants at this codon or neighboring codons: none. Population data: Highest MAF in Ashkenazi Jewish population: 0.18%. The variant was reported online in 33 of 121,946 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 18 of 4,892 individuals of Ashkenazi Jewish descent (MAF=0.18%), 9 of 55,151 individuals of European descent, 2 of 16,689 individuals of Latino descent, 1 of 15,341 individuals of South Asian descent and 3 of 2,703 individuals of "other" descent. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease.

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