Total submissions: 16
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory for Molecular Medicine, |
RCV000040927 | SCV000064618 | uncertain significance | not specified | 2015-08-08 | criteria provided, single submitter | clinical testing | Variant classified as Uncertain Significance - Favor Benign. The p.Thr31863Met v ariant in TTN has been identified in 0.1% (70/66688) of European chromosomes and 0.1% (11/11554) of Latino chromosomes by the Exome Aggregation Consortium (ExAC , http://exac.broadinstitute.org; dbSNP rs192001910). Computational prediction t ools and conservation analysis do not provide strong support for or against an i mpact to the protein. In summary, while the clinical significance of the p.Thr31 863Met variant is uncertain, its frequency suggests that it is more likely to be benign. |
Gene |
RCV000725429 | SCV000237910 | likely benign | not provided | 2020-11-19 | criteria provided, single submitter | clinical testing | This variant is associated with the following publications: (PMID: 23396983) |
Eurofins Ntd Llc |
RCV000725429 | SCV000336875 | uncertain significance | not provided | 2015-11-23 | criteria provided, single submitter | clinical testing | |
Invitae | RCV001082764 | SCV000555575 | likely benign | Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J | 2024-01-25 | criteria provided, single submitter | clinical testing | |
Athena Diagnostics | RCV000725429 | SCV000615965 | likely benign | not provided | 2020-06-26 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV000619030 | SCV000737132 | likely benign | Cardiovascular phenotype | 2019-07-31 | criteria provided, single submitter | clinical testing | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. |
ARUP Laboratories, |
RCV000040927 | SCV001157329 | uncertain significance | not specified | 2019-05-11 | criteria provided, single submitter | clinical testing | The TTN c.103292C>T; p.Thr34431Met variant (rs192001910; ClinVar Variation ID: 47658) is rare in the general population (<1% 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.Thr34431Met variant cannot be determined with certainty. References: Begay RL et al. Role of Titin Missense Variants in Dilated Cardiomyopathy. J Am Heart Assoc. 2015 Nov 13;4(11). Herman DS et al. Truncations of titin causing dilated cardiomyopathy. N Engl J Med. 2012 Feb 16;366(7):619-28. Linke and Hamdani. Gigantic business: titin properties and function through thick and thin. Circ Res 2014; 114(6): 1052-1068. |
Illumina Laboratory Services, |
RCV001135484 | SCV001295266 | 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. |
Illumina Laboratory Services, |
RCV001135485 | SCV001295267 | 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, |
RCV001135486 | SCV001295268 | 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, |
RCV001135487 | SCV001295269 | 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, |
RCV001135488 | SCV001295270 | 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. |
CHEO Genetics Diagnostic Laboratory, |
RCV001170292 | SCV001332856 | likely benign | Cardiomyopathy | 2018-04-26 | criteria provided, single submitter | clinical testing | |
Mayo Clinic Laboratories, |
RCV000725429 | SCV001653314 | uncertain significance | not provided | 2019-12-26 | criteria provided, single submitter | clinical testing | |
Ce |
RCV000725429 | SCV001746670 | uncertain significance | not provided | 2021-06-01 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000040927 | SCV003934135 | likely benign | not specified | 2023-05-23 | criteria provided, single submitter | clinical testing | Variant summary: TTN c.95588C>T (p.Thr31863Met) results in a non-conservative amino acid change located in the M-band region of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00065 in 248856 control chromosomes, predominantly at a frequency of 0.00098 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 3-fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.95588C>T has been reported in the literature in settings of multigene panel testing in individuals affected with Dilated Cardiomyopathy, Hypertrophic Cardiomyopathy, and a case of sudden unexplained death, without strong evidence for causality (e.g. Lopes_2013, Campuzano_2015) . These reports do 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. The following publications have been ascertained in the context of this evaluation (PMID: 26516846, 23396983). Twelve submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as benign (n=1)/likely benign (n=5) or VUS (n=6). Based on the evidence outlined above, the variant was classified as likely benign. |