ClinVar Miner

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

dbSNP: rs397517583
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Total submissions: 12
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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
Invitae 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

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