Total submissions: 26
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Cardiovascular Biomedical Research Unit, |
RCV000209622 | SCV000189682 | uncertain significance | Primary dilated cardiomyopathy | 2014-10-08 | criteria provided, single submitter | research | This TTN truncating variant (TTNtv) was identified in one individual in this cohort and is located in an exon that is highly expressed in the heart. In the seven cohorts assessed, TTNtv were found in 14% of ambulant DCM, 22% end-stage or familial DCM, and 2% controls. Heterozygous nonsense, frameshift and canonical splice-disrupting variants found in constitutive and other highly utilised exons are highly likely to be pathogenic when identified in individuals with phenotypically confirmed DCM. TTNtv found incidentally in healthy individuals (excluding familial assessment of DCM relatives) are thought to have low penetrance, particularly when identified in exons that are not constitutively expressed in the heart. |
Laboratory for Molecular Medicine, |
RCV000154951 | SCV000204633 | benign | not specified | 2018-11-09 | criteria provided, single submitter | clinical testing | proposed classification - variant undergoing re-assessment, contact laboratory |
Gene |
RCV000725365 | SCV000237174 | likely benign | not provided | 2021-01-18 | criteria provided, single submitter | clinical testing | This variant is associated with the following publications: (PMID: 25589632) |
Blueprint Genetics | RCV000154951 | SCV000264280 | likely benign | not specified | 2015-06-25 | criteria provided, single submitter | clinical testing | |
Labcorp Genetics |
RCV001085058 | SCV000542551 | likely benign | Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J | 2024-01-22 | criteria provided, single submitter | clinical testing | |
Eurofins Ntd Llc |
RCV000725365 | SCV000700951 | uncertain significance | not provided | 2018-06-01 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV000621229 | SCV000735436 | likely benign | Cardiovascular phenotype | 2019-12-18 | 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. |
CHEO Genetics Diagnostic Laboratory, |
RCV000769013 | SCV000900386 | benign | Cardiomyopathy | 2020-05-08 | criteria provided, single submitter | clinical testing | |
Athena Diagnostics | RCV000725365 | SCV001146406 | likely benign | not provided | 2018-12-29 | criteria provided, single submitter | clinical testing | |
ARUP Laboratories, |
RCV000725365 | SCV001157839 | uncertain significance | not provided | 2021-03-10 | criteria provided, single submitter | clinical testing | The TTN c.44281C>T; p.Pro14761Ser variant (rs192766485; ClinVar Variation ID: 178217) is rare in the general population (<1% allele frequency in the Genome Aggregation Database) and has been reported in a cohort of individuals with dilated cardiomyopathy (Roberts 2015). 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.Pro14761Ser 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. Roberts AM at al. Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease. Sci Transl Med. 2015 Jan 14;7(270):270ra6. |
Illumina Laboratory Services, |
RCV001130087 | SCV001289650 | benign | Tibial muscular dystrophy | 2017-04-27 | criteria provided, single submitter | clinical testing | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. |
Illumina Laboratory Services, |
RCV001130088 | SCV001289651 | uncertain significance | Autosomal recessive limb-girdle muscular dystrophy type 2J | 2017-04-27 | criteria provided, single submitter | clinical testing | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. |
Illumina Laboratory Services, |
RCV001130089 | SCV001289652 | uncertain significance | Early-onset myopathy with fatal cardiomyopathy | 2017-04-27 | criteria provided, single submitter | clinical testing | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. |
Illumina Laboratory Services, |
RCV000415667 | SCV001290375 | uncertain significance | Dilated cardiomyopathy 1G | 2017-04-27 | criteria provided, single submitter | clinical testing | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. |
Illumina Laboratory Services, |
RCV001130785 | SCV001290376 | benign | Myopathy, myofibrillar, 9, with early respiratory failure | 2017-04-27 | criteria provided, single submitter | clinical testing | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000154951 | SCV001448577 | likely benign | not specified | 2020-11-02 | criteria provided, single submitter | clinical testing | Variant summary: TTN c.36577C>T (p.Pro12193Ser) results in a non-conservative amino acid change located in the I band domain (https://www.cardiodb.org/titin/titin_transcripts.php) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00066 in 248262 control chromosomes, predominantly at a frequency of 0.0011 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), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.36577C>T has been reported in the literature in individuals affected with sudden unexplained death/Left Ventricular Non-Compaction (Campuzano_2015). However, 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. Twelve ClinVar submitters (evaluation after 2014) cite the variant as likely benign/benign (n=7) or uncertain significance (n=5). Based on the evidence outlined above, the variant was classified as likely benign. |
Ce |
RCV000725365 | SCV001747282 | uncertain significance | not provided | 2021-06-01 | criteria provided, single submitter | clinical testing | |
Knight Diagnostic Laboratories, |
RCV000415667 | SCV000493821 | uncertain significance | Dilated cardiomyopathy 1G | 2015-12-04 | no assertion criteria provided | clinical testing | |
Knight Diagnostic Laboratories, |
RCV000415702 | SCV000493822 | uncertain significance | Hypertrophic cardiomyopathy 9 | 2015-12-04 | no assertion criteria provided | clinical testing | |
Department of Pathology and Laboratory Medicine, |
RCV000725365 | SCV001551593 | uncertain significance | not provided | no assertion criteria provided | clinical testing | The TTN p.Pro12193Ser variant was not identified in the literature but was identified in dbSNP (ID: rs192766485), LOVD 3.0 and ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, EGL Genetics and three other laboratories, as likely benign by Blueprint Genetics and GeneDx and as benign by Laboratory for Molecular Medicine). The variant was identified in control databases in 181 of 279630 chromosomes at a frequency of 0.0006473 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 142 of 127884 chromosomes (freq: 0.00111), Other in 7 of 7120 chromosomes (freq: 0.000983), Latino in 24 of 35264 chromosomes (freq: 0.000681) and African in 8 of 24182 chromosomes (freq: 0.000331), but was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), or South Asian populations. The p.Pro12193 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The p.Pro12193Ser variant occurs in the last base of the exon; this position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. However, three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a greater than 10% difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. | |
Diagnostic Laboratory, |
RCV000725365 | SCV001741100 | likely benign | not provided | no assertion criteria provided | clinical testing | ||
Laboratory of Diagnostic Genome Analysis, |
RCV000725365 | SCV001799765 | likely benign | not provided | no assertion criteria provided | clinical testing | ||
Clinical Genetics, |
RCV000725365 | SCV001922149 | likely benign | not provided | no assertion criteria provided | clinical testing | ||
Genome Diagnostics Laboratory, |
RCV000725365 | SCV001932235 | likely benign | not provided | no assertion criteria provided | clinical testing | ||
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, |
RCV000725365 | SCV001953568 | likely benign | not provided | no assertion criteria provided | clinical testing | ||
Clinical Genetics DNA and cytogenetics Diagnostics Lab, |
RCV000725365 | SCV001972027 | likely benign | not provided | no assertion criteria provided | clinical testing |