Submissions for variant NM_001267550.2(TTN):c.107753G>A (p.Cys35918Tyr)

gnomAD frequency: 0.00032  dbSNP: rs193212275

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000039843	SCV000063534	uncertain significance	not specified	2013-06-27	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The Cys33350Tyr var iant in TTN has been identified by our laboratory in 1 Black individual with iso lated right atrial enlargement and 1 Black individual with HCM (LMM unpublished data). It has also been identified in 1.1% (2/176) of Yoruba chromosomes by the 1000 Genomes Project (dbSNP rs193212275) and 0.1% (4/3778) of African American c hromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/E VS/). Computational analyses (biochemical amino acid properties, conservation, P olyPhen2, and SIFT) suggest that this variant may impact the protein, though thi s information is not predictive enough to determine pathogenicity. Although the frequency of this variant suggests that it may be more likely benign, it is too low to confidently rule out a disease-causing role. Additional studies are neede d to fully assess the clinical significance of this variant.
GeneDx	RCV001509175	SCV000237979	likely benign	not provided	2020-03-10	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25163546)
Invitae	RCV000464810	SCV000542306	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2018-01-23	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769835	SCV000901261	benign	Cardiomyopathy	2019-09-06	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV001509175	SCV001715739	uncertain significance	not provided	2021-02-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002408527	SCV002675678	likely benign	Cardiovascular phenotype	2020-07-14	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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	RCV001509175	SCV003819101	uncertain significance	not provided	2019-12-02	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003904953	SCV004727565	uncertain significance	TTN-related condition	2023-10-27	criteria provided, single submitter	clinical testing	The TTN c.107753G>A variant is predicted to result in the amino acid substitution p.Cys35918Tyr. This variant has been reported in an individual with dilated cardiomyopathy (Table S6, Haas et al. 2015. PubMed ID: 25163546). This variant is reported in 0.11% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-179391962-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.