Submissions for variant NM_001267550.2(TTN):c.39212-9C>A

dbSNP: rs373056460

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000156462	SCV000206181	likely benign	not specified	2019-02-13	criteria provided, single submitter	clinical testing	The c.31910-9C>A variant in TTN is classified as likely benign because it has been identified in 0.095% (33/34446) of Latino chromosomes by gnomAD (https://gnomad.broadinstitute.org) and computational tools do not suggest an impact on splicing. ACMG/AMP Criteria applied: BS1, BP4.
Invitae	RCV000468721	SCV000555221	likely benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-11-24	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852864	SCV000995598	likely benign	Cardiomyopathy	2018-12-13	criteria provided, single submitter	clinical testing
GeneDx	RCV001555162	SCV001776529	likely benign	not provided	2020-08-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000156462	SCV001821376	benign	not specified	2021-08-23	criteria provided, single submitter	clinical testing	Variant summary: TTN c.31910-9C>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00014 in 248766 control chromosomes, predominantly at a frequency of 0.00096 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 2.5-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 Latino origin. To our knowledge, no occurrence of c.31910-9C>A in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. A co-occurrence with a pathogenic variant has been reported (MYBPC3 c.1504C>T, p.Arg502Trp; Internal testing), providing supporting evidence for a benign role. Four ClinVar submitters (evaluation after 2014) cite the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign.
Genome-Nilou Lab	RCV001840192	SCV002101231	benign	Autosomal recessive limb-girdle muscular dystrophy type 2J	2021-09-10	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001840193	SCV002101232	benign	Myopathy, myofibrillar, 9, with early respiratory failure	2021-09-10	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001840194	SCV002101233	benign	Early-onset myopathy with fatal cardiomyopathy	2021-09-10	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001840191	SCV002101234	benign	Tibial muscular dystrophy	2021-09-10	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004544454	SCV004776149	likely benign	TTN-related disorder	2020-06-05	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).