Submissions for variant NM_001267550.2(TTN):c.106349C>G (p.Thr35450Ser)

gnomAD frequency: 0.00017  dbSNP: rs371022420

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001561125	SCV001783664	likely benign	not provided	2019-01-16	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 31983221)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001806240	SCV002051144	uncertain significance	not specified	2021-12-15	criteria provided, single submitter	clinical testing	Variant summary: TTN c.98645C>G (p.Thr32882Ser) results in a conservative amino acid change located in the M-band domain of the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.5e-05 in 245540 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in TTN causing Dilated Cardiomyopathy (4.5e-05 vs 0.00039), allowing no conclusion about variant significance. c.98645C>G has been reported in the literature in individuals affected with Dilated Cardiomyopathy (Mazzarotto_2020). This report does 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. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV002421196	SCV002677275	likely benign	Cardiovascular phenotype	2020-07-23	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.
Revvity Omics, Revvity	RCV001561125	SCV003820221	uncertain significance	not provided	2020-12-25	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004536186	SCV004118916	uncertain significance	TTN-related disorder	2023-08-23	criteria provided, single submitter	clinical testing	The TTN c.106349C>G variant is predicted to result in the amino acid substitution p.Thr35450Ser. This variant has been reported in an individual with dilated cardiomyopathy; however, pathogenicity was not established (Table S3, chr2:179394993 in Mazzarotto F et al 2020. PubMed ID: 31983221). This variant is reported in 0.037% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-179394993-G-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.