Submissions for variant NM_001267550.2(TTN):c.12145C>T (p.Pro4049Ser)

gnomAD frequency: 0.00016  dbSNP: rs201888760

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172704	SCV000051258	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041086	SCV000064777	uncertain significance	not specified	2012-03-20	criteria provided, single submitter	clinical testing	The Pro3811Ser variant in TTN has been identified in 1/6622 European American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS). Conservation and computational tools are limited or unavailable for this variant. Additional information is needed to assess the cli nical significance of this variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000560737	SCV000642654	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-12-07	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000172704	SCV000701607	uncertain significance	not provided	2017-05-16	criteria provided, single submitter	clinical testing
GeneDx	RCV000172704	SCV000731018	likely benign	not provided	2021-02-03	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000041086	SCV000844618	likely benign	not specified	2024-04-16	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000172704	SCV001153104	likely benign	not provided	2024-11-01	criteria provided, single submitter	clinical testing	TTN: BP4
Ambry Genetics	RCV002426582	SCV002743178	likely benign	Cardiovascular phenotype	2019-09-12	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	RCV004537139	SCV004113284	uncertain significance	TTN-related disorder	2023-09-13	criteria provided, single submitter	clinical testing	The TTN c.12145C>T variant is predicted to result in the amino acid substitution p.Pro4049Ser. This variant was reported along with a truncating TTN variant in an individual with dilated cardiomyopathy; however, no additional studies were performed to help assess the pathogenicity of this variant (Table S4, Franaszczyk et al. 2017. PubMed ID: 28045975). This variant is reported in 0.11% of alleles in individuals of Ashkenazi Jewish descent in gnomAD, including one homozygote in this population database (http://gnomad.broadinstitute.org/variant/2-179605815-G-A). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003486619	SCV004239818	benign	Cardiomyopathy	2023-06-08	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000172704	SCV001552712	uncertain significance	not provided		no assertion criteria provided	clinical testing	The TTN p.Pro3878Ser variant was identified in 1 of 144 proband chromosomes (frequency: 0.0069) from an individual with dilated cardiomyopathy who also carried a TTN truncating mutation (Franaszczyk_2017_PMID:28045975). The variant was identified in dbSNP (ID: rs201888760) and ClinVar (classified as likely benign by Biesecker Lab and GeneDx and uncertain significance by Invitae, Athena Diagnostics Inc, Laboratory for Molecular Medicine and EGL Genetic Diagnostics). The variant was identified in control databases in 104 of 279690 chromosomes (1 homozygous) at a frequency of 0.0003718 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 11 of 10328 chromosomes (freq: 0.001065), Other in 7 of 7110 chromosomes (freq: 0.000985), European (non-Finnish) in 63 of 127606 chromosomes (freq: 0.000494), South Asian in 13 of 30594 chromosomes (freq: 0.000425), Latino in 6 of 35360 chromosomes (freq: 0.00017) and African in 4 of 24182 chromosomes (freq: 0.000165), but was not observed in the East Asian, or European (Finnish) populations. The p.Pro3878 residue has limited species conservation data and computational analyses (BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.