Submissions for variant NM_001267550.2(TTN):c.98959_98960delinsCT (p.Ser32987Leu)

dbSNP: rs727504588

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000155761	SCV000205472	uncertain significance	not specified	2014-01-21	criteria provided, single submitter	clinical testing	The Ser30419Leu variant in TTN has now been identified by our laboratory in 1 in fant with DCM and 1 adult with HCM. It was not identified in large population st udies. Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. Additional information is needed to fully assess the clin ical significance of the Ser30419Leu variant.
Invitae	RCV000543884	SCV000644002	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-12-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000621722	SCV000735614	likely benign	Cardiovascular phenotype	2023-02-01	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.
Fulgent Genetics, Fulgent Genetics	RCV000764302	SCV000895321	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
Mayo Clinic Laboratories, Mayo Clinic	RCV001508101	SCV001714025	uncertain significance	not provided	2019-11-18	criteria provided, single submitter	clinical testing
GeneDx	RCV001508101	SCV001825452	likely benign	not provided	2021-05-20	criteria provided, single submitter	clinical testing	Observed in 21/125,412 (0.01%) alleles from individuals of European background (Lek et al., 2016); This variant is associated with the following publications: (PMID: 25332820)
Revvity Omics, Revvity	RCV001508101	SCV003824227	uncertain significance	not provided	2023-03-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000155761	SCV003844826	uncertain significance	not specified	2023-02-15	criteria provided, single submitter	clinical testing	Variant summary: TTN c.91255_91256delinsCT (p.Ser30419Leu) results in a non-conservative amino acid change located in the A-band region of the encoded protein sequence. Two of three in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9e-05 in 279158 control chromosomes. This frequency does not allow conclusions about variant significance. c.91255_91256delinsCT has been reported in the literature in individuals affected with dilated cardiomyopathy (Wasielewski_2014), hypertrophic cardiomyopathy (Burstein_2021), and pediatric-onset cardiomyopathy (Herkert_2020), however, co-segregation and co-occurrence data suggested the variant was not causative of disease in all cases. These reports do not provide unequivocal conclusions about association of the variant with Limb-Girdle Muscular Dystrophy, Type 2J. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) have cited the variant with conflicting assessments; 4 submitters classified the variant as uncertain significance, and one submitter classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003398810	SCV004111701	uncertain significance	TTN-related condition	2023-10-02	criteria provided, single submitter	clinical testing	The TTN c.98959_98960delinsCT variant is predicted to result in an in-frame deletion and insertion. This variant has been reported in an individual with dilated cardiomyopathy (aka p.Ser31346Leu, Wasielewski et al. 2014. PubMed ID: 25332820) and an individual with hypertrophic cardiomyopathy (aka p.Ser30419Leu, Table S2, Burstein et al. 2021. PubMed ID: 32746448). This variant was also observed in an individual with severe cardiac defects; however, a sibling that was also affected did not carry the variant (aka p.Ser30419Leu, Family 7, Herkert et al. 2020. PubMed ID: 32480058). This variant is reported in 0.017% of alleles in individuals of European (non-Finnish) descent in gnomAD as a multi-nucleotide variant (https://gnomad.broadinstitute.org/variant/2-179403703-A-G; https://gnomad.broadinstitute.org/variant/2-179403702-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.