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

gnomAD frequency: 0.00051  dbSNP: rs180975448

Total submissions: 22

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.
Labcorp Genetics (formerly Invitae), Labcorp	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