Submissions for variant NM_001267550.2(TTN):c.15496+1G>T

dbSNP: rs397517481

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV003883495	SCV001371400	uncertain significance	not provided	2020-06-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001330277	SCV001521912	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2J	2019-11-04	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Labcorp Genetics (formerly Invitae), Labcorp	RCV001376850	SCV001574036	pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-10-18	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 52 of the TTN gene. It is expected to disrupt RNA splicing and likely results in a truncated or disrupted TTN protein. This variant is present in population databases (no rsID available, gnomAD 0.0009%). Disruption of this splice site has been observed in individual(s) with autosomal recessive centronuclear myopathy (PMID: 23975875). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 404903). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant is located in the I band of TTN (PMID: 25589632). Truncating variants in this region have been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875, internal data). Truncating variants in this region have also been identified in individuals affected with autosomal dominant dilated cardiomyopathy and/or cardio-related conditions (PMID: 27869827, 32964742, internal data). For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004787710	SCV005398881	pathogenic	TTN-related myopathy	2022-03-31	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 truncating codon (PTC) are known to have reduced penetrance in DCM (PMID: 25589632). (I) 0211 - 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 (v2) <0.001 (1 heterozygote, 0 homozygotes). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0600 - Variant is located between exons within the annotated N-terminal I-band, which have PSI scores between 7 and 10 (PMID: 25589632). (I) 0703 - Another canonical splice variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. This variant (c.15496+1G>A) has been reported as pathogenic and likely pathogenic, and observed in several compound heterozygous individuals with centronuclear myopathy (CM) or congenital titanopathy, with or without multiminicore disease (ClinVar, PMID: 23975875, PMID: 29691892, PMID: 31053406). (SP) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic, likely pathogenic and as a VUS, and observed in at least two individuals with either limb girdle muscular dystrophy or congenital CM. The individual with congenital CM was heterozygous, with no identified variant in trans (ClinVar, personal communication). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1206 - This variant has been shown to be paternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV004813098	SCV005438582	likely pathogenic	Dilated cardiomyopathy 1G	2024-12-18	criteria provided, single submitter	clinical testing