Submissions for variant NM_001267550.2(TTN):c.84398A>G (p.Asn28133Ser)

gnomAD frequency: 0.00001  dbSNP: rs727505053

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000156482	SCV000206201	uncertain significance	not specified	2014-05-01	criteria provided, single submitter	clinical testing	The Asn25565Ser variant in TTN has not been previously reported in individuals w ith cardiomyopathy or in large population studies. Computational prediction tool s and conservation analysis do not provide strong support for or against an impa ct to the protein. In summary, the clinical significance of this variant is unce rtain.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000459869	SCV000543084	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2016-10-31	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000764308	SCV000895327	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J; Tibial muscular dystrophy; Myopathy, myofibrillar, 9, with early respiratory failure; Early-onset myopathy with fatal cardiomyopathy; Hypertrophic cardiomyopathy 9	2018-10-31	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000156482	SCV001158191	uncertain significance	not specified	2019-03-01	criteria provided, single submitter	clinical testing	The TTN c.76694A>G; p.Asn25565Ser variant (rs727505053; ClinVar Variation ID: 179686) is rare in the general population (<1% allele frequency in the Genome Aggregation Database) and has not been reported in the medical literature in association with dilated cardiomyopathy (DCM) or other TTN-related disease. The clinical relevance of rare missense variants in this gene, which are identified on average once per individual sequenced in affected populations (Herman 2012), is not well understood. Yet, evidence suggests that the vast majority of such missense variants do not contribute to the clinical outcome of DCM (Begay 2015). Thus, the clinical significance of the p.Asn25565Ser variant cannot be determined with certainty.
Ambry Genetics	RCV002345519	SCV002650195	likely benign	Cardiovascular phenotype	2020-03-26	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Revvity Omics, Revvity	RCV003137682	SCV003824203	uncertain significance	not provided	2021-01-28	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004535010	SCV004115099	uncertain significance	TTN-related disorder	2022-10-11	criteria provided, single submitter	clinical testing	The TTN c.84398A>G variant is predicted to result in the amino acid substitution p.Asn28133Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.010% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-179426461-T-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.