Submissions for variant NM_001267550.2(TTN):c.96998G>A (p.Arg32333His)

gnomAD frequency: 0.00099  dbSNP: rs138846756

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040846	SCV000064537	likely benign	not specified	2012-04-18	criteria provided, single submitter	clinical testing	Arg29765His in Exon 297 of TTN: This variant is not expected to have clinical si gnificance because it has been identified in 0.5% (17/3292) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs138846756). Arg29765His in Exon 297 of TTN (allele frequency = 0.5%, 17/3292; dbSNP rs138846756) **
GeneDx	RCV001528674	SCV000237825	likely benign	not provided	2020-06-05	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24503780)
Ambry Genetics	RCV000247847	SCV000319159	likely benign	Cardiovascular phenotype	2018-07-05	criteria provided, single submitter	clinical testing	Subpopulation frequency in support of benign classification
Eurofins Ntd Llc (ga)	RCV000040846	SCV000332163	likely benign	not specified	2015-06-11	criteria provided, single submitter	clinical testing
Invitae	RCV000461503	SCV000555180	likely benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-31	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798202	SCV002043080	benign	Cardiomyopathy	2020-12-22	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001839741	SCV002102077	benign	Autosomal recessive limb-girdle muscular dystrophy type 2J	2021-09-10	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001839742	SCV002102078	benign	Myopathy, myofibrillar, 9, with early respiratory failure	2021-09-10	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001839743	SCV002102079	benign	Early-onset myopathy with fatal cardiomyopathy	2021-09-10	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001839740	SCV002102080	benign	Tibial muscular dystrophy	2021-09-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000040846	SCV002500764	likely benign	not specified	2022-03-29	criteria provided, single submitter	clinical testing	Variant summary: TTN c.89294G>A (p.Arg29765His) results in a non-conservative amino acid change located in the A-band domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00035 in 247604 control chromosomes, predominantly at a frequency of 0.004 within the African or African-American subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 10 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. c.89294G>A has been reported in the literature in individuals affected with Dilated Cardiomyopathy, HCM and sudden unexplained death, without strong evidence for causality (Pugh_2014, Campuzano_2015, Burstein_2021). These reports do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics	RCV003242972	SCV003940067	likely benign	Inborn genetic diseases	2023-05-25	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.
PreventionGenetics, part of Exact Sciences	RCV003904976	SCV004720240	likely benign	TTN-related condition	2021-02-03	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).
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001528674	SCV001740814	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001528674	SCV001924759	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001528674	SCV001930597	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001528674	SCV001968974	likely benign	not provided		no assertion criteria provided	clinical testing