Submissions for variant NM_001267550.2(TTN):c.92152+7T>G

gnomAD frequency: 0.00002  dbSNP: rs574211300

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000547021	SCV000643896	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-04-14	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV001528902	SCV005188106	uncertain significance	not provided		criteria provided, single submitter	not provided
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004787887	SCV005398367	uncertain significance	Dilated cardiomyopathy 1G	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0103 - Loss of function is an established mechanism of disease while dominant negative is a likely mechanism as not all truncated transcripts in dilated cardiomyopathy (DCM) individuals undergo nonsense mediated decay (PMID: 25589632). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance. Protein truncating variants in this gene are known to have reduced penetrance in DCM (PMID: 25589632). (I) 0212 - Non-canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (10 heterozygotes, 0 homozygotes). (SP) 0506 - Abnormal splicing is not predicted and nucleotide is poorly conserved. (SB) 0705 - No comparable splice variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been previously reported as a VUS (ClinVar), and as likely benign and benign (LOVD). (I) 0906 - Segregation evidence for this variant is inconclusive. This variant has also been observed in this individual's affected brother, however more meioses are required to establish the significance of this finding (VCGS). (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001528902	SCV001741443	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001727745	SCV001970994	benign	not specified		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004735609	SCV005350297	likely benign	TTN-related disorder	2024-06-27	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).