Submissions for variant NM_001267550.2(TTN):c.59318A>G (p.Glu19773Gly)

gnomAD frequency: 0.00083  dbSNP: rs371719028

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172655	SCV000054973	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040419	SCV000064110	uncertain significance	not specified	2014-06-18	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The Glu17205Gly var iant in TTN has been identified by our laboratory in 1 African American individu al with DCM and possible LVNC. This variant has also been identified in 0.2% (9/ 3840) of African American chromosomes by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS/; dbSNP rs371719028). Computational prediction too ls and conservation analysis do not provide strong support for or against an imp act to the protein. In summary, while the clinical significance of the Glu17205G ly variant is uncertain, its frequency suggests that it is more likely to be ben ign.
GeneDx	RCV000172655	SCV000237354	likely benign	not provided	2021-04-29	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23861362)
Eurofins Ntd Llc (ga)	RCV000172655	SCV000333438	uncertain significance	not provided	2015-07-31	criteria provided, single submitter	clinical testing
Invitae	RCV001085920	SCV000555377	likely benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000172655	SCV001152845	likely benign	not provided	2023-07-01	criteria provided, single submitter	clinical testing	TTN: BP4
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000040419	SCV001437319	benign	not specified	2020-09-25	criteria provided, single submitter	clinical testing	Variant summary: TTN c.51614A>G (p.Glu17205Gly) results in a non-conservative amino acid change located in the A-band region of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00022 in 279750 control chromosomes, predominantly at a frequency of 0.0026 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 6.5-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 African or African-American origin. To our knowledge, no occurrence of c.51614A>G in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely benign (2x), or VUS (2x). Based on the evidence outlined above, the variant was classified as benign.
Ambry Genetics	RCV002321525	SCV002609382	likely benign	Cardiovascular phenotype	2019-03-04	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.
PreventionGenetics, part of Exact Sciences	RCV004541163	SCV004765932	likely benign	TTN-related disorder	2024-02-05	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).