Submissions for variant NM_001267550.2(TTN):c.107915G>T (p.Ser35972Ile)

gnomAD frequency: 0.00014  dbSNP: rs397517478

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000039845	SCV000063536	likely benign	not specified	2018-12-03	criteria provided, single submitter	clinical testing	The p.Ser33404Ile variant is classified as likely benign because it has been ide ntified in 0.01% (13/128318) of European chromosomes by gnomAD (http://gnomad.br oadinstitute.org). Serine (Ser) at position 33404Ile is not conserved in mammals or evolutionarily distant species and 1 mammal (star-nosed mole) carries an iso leucine (Ile) at this position, raising the possibility that this change may be tolerated. Additional computational prediction tools suggest that this variant m ay not impact the protein. ACMG/AMP Criteria applied: BS1_Supporting, BP4.
Eurofins Ntd Llc (ga)	RCV000725604	SCV000338094	uncertain significance	not provided	2015-12-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002415479	SCV002677061	likely benign	Cardiovascular phenotype	2020-05-27	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.
Athena Diagnostics Inc	RCV000725604	SCV002770634	uncertain significance	not provided	2022-08-22	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000725604	SCV003826732	uncertain significance	not provided	2022-04-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000039845	SCV003934108	uncertain significance	not specified	2023-05-18	criteria provided, single submitter	clinical testing	Variant summary: TTN c.100211G>T (p.Ser33404Ile) results in a non-conservative amino acid change located in the M-band region of the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 248994 control chromosomes (i.e., 17 heterozygous carriers; gnomAD). This frequency is not higher than the estimated maximum expected for a pathogenic variant in TTN causing Dilated Cardiomyopathy (6.8e-05 vs 0.00039), allowing no conclusion about variant significance. c.100211G>T has been reported in the literature in at least one individual affected with coronary heart disease (e.g., Guelly_2021). 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. The following publication was ascertained in the context of this evaluation (PMID: 33552729). Five ClinVar submitters (evaluation after 2014) have reported the variant with conflicting assessments: 3 classify the variant as uncertain significance, and 2 classify the variant as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
CeGaT Center for Human Genetics Tuebingen	RCV000725604	SCV004150164	uncertain significance	not provided	2023-02-01	criteria provided, single submitter	clinical testing	TTN: PM2, BP4