Submissions for variant NM_001267550.2(TTN):c.46065G>C (p.Lys15355Asn)

dbSNP: rs397517583

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040265	SCV000063956	uncertain significance	not specified	2015-12-18	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Lys12787Asn v ariant in TTN has been reported by our laboratory in 2 individuals (1 HCM and 1 ARVC with reduced LV function). Both individuals carried a disease-causing varia nt in another gene and p.Lys12787Asn did not segregate with ARVC in an affected family member. It has been identified in 0.24% (40/16444) of South Asian chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs397517583). Computational prediction tools and conservation analysis su ggest that this variant may impact the protein, though this information is not p redictive enough to determine pathogenicity. In summary, while the clinical sign ificance of the p.Lys12787Asn variant is uncertain, its frequency suggests that it is more likely to be benign.
Illumina Laboratory Services, Illumina	RCV000347554	SCV000423199	uncertain significance	Dilated Cardiomyopathy, Dominant	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000407706	SCV000423200	uncertain significance	Limb-girdle muscular dystrophy, recessive	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000303308	SCV000423201	uncertain significance	Hypertrophic cardiomyopathy	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000358217	SCV000423202	uncertain significance	Early-onset myopathy with fatal cardiomyopathy	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000406048	SCV000423203	uncertain significance	Myopathy, myofibrillar, 9, with early respiratory failure	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000304633	SCV000423204	uncertain significance	Tibial muscular dystrophy	2016-06-14	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000727270	SCV000707110	uncertain significance	not provided	2017-03-23	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770026	SCV000901452	benign	Cardiomyopathy	2017-10-17	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001079806	SCV001009847	likely benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-06-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000040265	SCV001448541	benign	not specified	2020-11-17	criteria provided, single submitter	clinical testing	Variant summary: TTN c.38361G>C (p.Lys12787Asn) results in a non-conservative amino acid change located in the I-band region of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0003 in 247648 control chromosomes, predominantly at a frequency of 0.0024 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 6-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 South Asian origin. The variant, c.38361G>C, has been reported in the literature in an individual affected with Dilated Cardiomyopathy, however this patient also had Wolff-Parkinson-White (WPW) syndrome and glycogen accumulation noted during cardiac transplant, consistent with Danon disease, in addition, in this patient a co-occurrence with another pathogenic variant (LAMP2 exon8-9 del) could explain the disease phenotype (Ceyhan-Birsoy_2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign (1x), likely benign (1x), VUS (3x)). Based on the evidence outlined above, the variant was classified as benign.
GeneDx	RCV000727270	SCV001784536	likely benign	not provided	2021-01-08	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004541156	SCV004795021	likely benign	TTN-related disorder	2022-07-28	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).