Submissions for variant NM_001267550.2(TTN):c.32653A>G (p.Met10885Val)

dbSNP: rs200732179

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000714015	SCV000844678	uncertain significance	not provided	2017-11-29	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000714015	SCV000855271	uncertain significance	not provided	2017-09-27	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001332825	SCV001525251	uncertain significance	Early-onset myopathy with fatal cardiomyopathy	2020-09-10	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Revvity Omics, Revvity	RCV000714015	SCV003825576	uncertain significance	not provided	2022-04-02	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000714015	SCV005198924	uncertain significance	not provided	2022-12-19	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000714015	SCV001550384	uncertain significance	not provided		no assertion criteria provided	clinical testing	The TTN p.Met9641Val variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs200732179) and in ClinVar (classified as a VUS by Athena Diagnostics and EGL Genetics). The variant was also identified in control databases in 35 of 248836 chromosomes at a frequency of 0.000141 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 28 of 112814 chromosomes (freq: 0.000248), European (Finnish) in 5 of 21540 chromosomes (freq: 0.000232), Other in 1 of 6038 chromosomes (freq: 0.000166) and African in 1 of 15466 chromosomes (freq: 0.000065); it was not observed in the Latino, Ashkenazi Jewish, East Asian or South Asian populations. The p.Met9641 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, 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 (MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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.