Submissions for variant NM_001267550.2(TTN):c.5577G>T (p.Arg1859Ser)

gnomAD frequency: 0.00010  dbSNP: rs551538420

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000185170	SCV000238008	uncertain significance	not provided	2016-11-15	criteria provided, single submitter	clinical testing	The R1859S variant of uncertain significance in the TTN gene has been previously reported in a three year-old male with sudden cardiac death while sleeping; however, he was found to harbor a second variant in the TTN gene, and no segregation data was provided (Campuzano et al., 2014). Although the R1859S variant has been identified in two other individuals who were referred for cardiogenetic testing at GeneDx, they were also found to harbor other TTN variants. Furthermore, segregation data is absent for these individuals due to the lack of clinical information provided and insufficient participation by informative family members. This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R1859S variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution also occurs at a position that is conserved across species. Consequently, the majority of in silico tools predict the R1859S variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae	RCV000643082	SCV000764769	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-10-03	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770132	SCV000901558	uncertain significance	Cardiomyopathy	2015-11-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002222433	SCV002500568	uncertain significance	not specified	2022-03-21	criteria provided, single submitter	clinical testing	Variant summary: TTN c.5577G>T (p.Arg1859Ser) results in a non-conservative amino acid change located in the near Z-disk / I-band region of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 251294 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in TTN causing Dilated Cardiomyopathy (4.8e-05 vs 0.00039), allowing no conclusion about variant significance. c.5577G>T has been reported in the literature in a juvenile with sudden cardiac death (Campuzano_2014). 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. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV002478646	SCV002784149	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	2021-08-17	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000185170	SCV003825483	uncertain significance	not provided	2023-06-02	criteria provided, single submitter	clinical testing