Submissions for variant NM_133379.5(TTN):c.13364A>G (p.Lys4455Arg)

gnomAD frequency: 0.00029  dbSNP: rs142304137

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041022	SCV000064713	uncertain significance	not specified	2013-08-27	criteria provided, single submitter	clinical testing	The Lys4455Arg variant in TTN has been identified by our laboratory in 1 Caucasi an individual with LVNC and bidirectional VT and has been identified in 1/8588 E uropean American chromosomes by the NHLBI Exome Sequencing Project (http://evs.g s.washington.edu/EVS/; dbSNP rs142304137). Computational analyses are limited or unavailable for this variant. Additional information is needed to fully assess its clinical significance.
GeneDx	RCV000726846	SCV000238116	likely benign	not provided	2019-03-08	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23476865)
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000415195	SCV000492708	uncertain significance	Syncope; Hypertrophic cardiomyopathy	2015-10-29	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000726846	SCV000703597	uncertain significance	not provided	2018-05-22	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000726846	SCV001153134	likely benign	not provided	2022-07-01	criteria provided, single submitter	clinical testing	TTN: BP4
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001198289	SCV001369170	uncertain significance	Tibial muscular dystrophy	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000726846	SCV001552805	uncertain significance	not provided		no assertion criteria provided	clinical testing	The TTN p.Lys4455Arg variant was identified in the literature, however the frequency of this variant in an affected population was not provided. The variant was also identified in dbSNP (ID: rs142304137), ClinVar (conflicting interpretations of pathogenicity, associated with syncope and hypertrophic cardiomyopathy; classified as Uncertain Significance by Laboratory for Molecular Medicine at Partners Healthcare, Centre for Mendelian Genomics at University Medical Centre Ljubljana, EGL Genetic Diagnostics and classified as Likely Benign by GeneDx), and LOVD 3.0. The variant was not identified in the Cosmic database. The variant was identified in control databases in 110 of 280462 chromosomes at a frequency of 0.000392 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 30 of 30546 chromosomes (freq: 0.000982), European (non-Finnish) in 62 of 128212 chromosomes (freq: 0.000484), Other in 3 of 7108 chromosomes (freq: 0.000422), Latino in 13 of 35210 chromosomes (freq: 0.000369), African in 2 of 24318 chromosomes (freq: 0.000082), while the variant was not observed in the Ashkenazi Jewish, East Asian, and European (Finnish) populations. The variant was identified in a 5 year old asymptomatic female who presented with sinus bradycardia and was found to have exercise-induced bidirectional VT and a hypertrabeculated left ventricle (Egan_2013_PMID: 23476865). A pan cardiomyopathy microarray identified three missense variants in this individual: RYR2 p.Arg169Gln, CASQ2 p.Asp398del, and TTN p.Lys4455Arg (Egan_2013_PMID: 23476865). Four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE) predict a greater than 10% difference in splicing, specificically a decrease in 5’ splicing activity at the variant location. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000726846	SCV001743009	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000726846	SCV001798696	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000726846	SCV001955850	likely benign	not provided		no assertion criteria provided	clinical testing