Submissions for variant NM_001267550.2(TTN):c.38424del (p.Lys12809fs)

dbSNP: rs1553775991

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000642777	SCV000764464	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2019-07-18	criteria provided, single submitter	clinical testing	This sequence change results in a premature translational stop signal in the TTN gene (p.Lys12809Argfs*138). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the TTN protein. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with TTN-related disease. This variant is located in the I band of TTN (PMID: 25589632). Truncating variants in this region have been shown to be highly prevalent in the general population and unaffected individuals (PMID: 26701604, 22335739). However, truncating variants in this region have also been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001262893	SCV001440929	uncertain significance	Early-onset myopathy with fatal cardiomyopathy	2019-01-01	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004788073	SCV005399225	pathogenic	Autosomal recessive titinopathy	2024-10-09	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is known mechanism of disease in this gene. In addition, dominant-negative is also a suggested mechanism. (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. Variants in this gene that result in a premature termination codon (PTC) are known to have reduced penetrance in DCM (PMID: 25589632). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0219 - This variant is non-coding in an alternative transcript. This variant is only coding in the meta-transcript (NM_001267550.1), and not in the cardiac (NM_003319.4) or skeletal muscle (NM_133378.4) transcripts. However recent literature has shown an association between variants only coding in the meta-transcript and autosomal recessive congenital titinopathy (PMID: 32778822). (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. At least ten other NMD-predicted variants in exons that are only coding in the meta-transcript have been reported as compound heterozygous or homozygous in over ten families with TTN-related congenital onset myopathy (ClinVar, PMID: 32778822, 29575618). (SP) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported twice as a VUS (ClinVar) and once as likely pathogenic in a compound heterozygous individual who presented with hypotonia and arthrogryposis at birth and was determined to have centronuclear myopathy (LOVD, PMID: 32778822). This variant was identified in trans with another NMD-predicted variant in this individual. (I) 0905 - No published segregation evidence has been identified for this variant. (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