ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.93005G>T (p.Ser31002Ile)

gnomAD frequency: 0.00051  dbSNP: rs180975448
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Total submissions: 22
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health RCV000172619 SCV000051297 likely benign not provided 2013-06-24 criteria provided, single submitter research
GeneDx RCV000172619 SCV000237772 likely benign not provided 2020-09-25 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 23396983, 23861362, 28771489)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000213505 SCV000272797 uncertain significance not specified 2015-04-08 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Ser28434Ile v ariant in TTN has not been previously reported in individuals with cardiomyopath y, but has been identified in 0.2% (103/66734) of European chromosomes by the Ex ome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs180975 448). Computational prediction tools and conservation analysis do not provide st rong support for or against an impact to the protein. In summary, while the clin ical significance of the p.Ser28434Ile variant is uncertain, its frequency sugge sts that it is more likely to be benign.
Invitae RCV001080503 SCV000286915 likely benign Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2024-02-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000244689 SCV000318972 uncertain significance Cardiovascular phenotype 2020-06-25 criteria provided, single submitter clinical testing The p.S28434I variant (also known as c.85301G>T) is located in coding exon 287 of the TTN gene. This alteration results from a G to T substitution at nucleotide position 85301. The serine at codon 28434 is replaced by isoleucine, an amino acid with some dissimilar properties. This variant has been reported in a hypertrophic cardiomyopathy cohort; however, clinical details were limited, and has also been reported as a secondary cardiac variant in an exome cohort (Lopes LR et al. J Med Genet. 2013;50:228-39; Ng D et al. Circ Cardiovasc Genet. 2013;6(4):337-46). Based on data from gnomAD, the T allele has an overall frequency of approximately 0.06% (175/279844) total alleles studied. The highest observed frequency was 0.12% (151/127670) of non-Finnish European alleles. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the majority of available evidence to date, this variant is unlikely to be pathogenic.
Genetic Services Laboratory, University of Chicago RCV000213505 SCV000597683 uncertain significance not specified 2016-05-16 criteria provided, single submitter clinical testing
Eurofins Ntd Llc (ga) RCV000172619 SCV000700957 uncertain significance not provided 2017-10-27 criteria provided, single submitter clinical testing
Athena Diagnostics RCV000172619 SCV001146534 likely benign not provided 2019-07-19 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000172619 SCV001152653 uncertain significance not provided 2023-12-01 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV001129597 SCV001289137 uncertain significance Dilated cardiomyopathy 1G 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina RCV001129598 SCV001289138 uncertain significance Early-onset myopathy with fatal cardiomyopathy 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina RCV001129599 SCV001289139 uncertain significance Autosomal recessive limb-girdle muscular dystrophy type 2J 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina RCV001129600 SCV001289140 benign Myopathy, myofibrillar, 9, with early respiratory failure 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina RCV001132342 SCV001292001 benign Tibial muscular dystrophy 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV001171247 SCV001333951 benign Cardiomyopathy 2018-07-06 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000213505 SCV002766498 likely benign not specified 2022-11-12 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000172619 SCV004225789 uncertain significance not provided 2023-04-27 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000172619 SCV004563857 uncertain significance not provided 2023-11-15 criteria provided, single submitter clinical testing The TTN c.93005G>T; p.Ser31002Ile variant (rs180975448; ClinVar Variation ID: 192143) is rare in the general population (<0.2% allele frequency in the Genome Aggregation Database) and has not been reported in the medical literature in association with dilated cardiomyopathy (DCM) or other TTN-related disease. The clinical relevance of rare missense variants in this gene, which are identified on average once per individual sequenced in affected populations (Herman 2012), is not well understood. Yet, evidence suggests that the vast majority of such missense variants do not contribute to the clinical outcome of DCM (Begay 2015). Thus, the clinical significance of the p.Ser31002Ile variant cannot be determined with certainty. Begay RL et al. Role of Titin Missense Variants in Dilated Cardiomyopathy. J Am Heart Assoc. 2015 Nov 13;4(11). PMID: 26567375. Herman DS et al. Truncations of titin causing dilated cardiomyopathy. N Engl J Med. 2012 Feb 16;366(7):619-28. PMID: 22335739. Linke WA and Hamdani N. Gigantic business: titin properties and function through thick and thin. Circ Res 2014; 114(6): 1052-1068. PMID: 24625729.
Clinical Genetics, Academic Medical Center RCV000213505 SCV001917202 benign not specified no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000172619 SCV001932408 likely benign not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000172619 SCV001958850 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000172619 SCV001967605 likely benign not provided no assertion criteria provided clinical testing

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