Submissions for variant NM_001267550.2(TTN):c.64898G>A (p.Arg21633Gln)

gnomAD frequency: 0.00016  dbSNP: rs141965360

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000714068	SCV000237423	uncertain significance	not provided	2023-06-08	criteria provided, single submitter	clinical testing	Reported in an infant with sudden unexpected death (Koh et al., 2022); In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Located in the A-band region of TTN in which the majority of loss of function variants have been associated with autosomal dominant titinopathies (Herman et al., 2012); This variant is associated with the following publications: (PMID: 26659599, 26934580, 28719003, 17344846, 35027292, 22335739)
Ambry Genetics	RCV000619156	SCV000735292	uncertain significance	Cardiovascular phenotype	2019-05-01	criteria provided, single submitter	clinical testing	The p.R12568Q variant (also known as c.37703G>A), located in coding exon 137 of the TTN gene, results from a G to A substitution at nucleotide position 37703. The arginine at codon 12568 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Athena Diagnostics Inc	RCV000714068	SCV000844735	uncertain significance	not provided	2017-11-10	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000714068	SCV000855199	uncertain significance	not provided	2018-03-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001328439	SCV001519572	uncertain significance	not specified	2021-03-15	criteria provided, single submitter	clinical testing	Variant summary: TTN c.57194G>A (p.Arg19065Gln) results in a conservative amino acid change located in the A-band region of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 248486 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in TTN causing Dilated Cardiomyopathy (0.00011 vs 0.00039), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.57194G>A in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Robert's Program, Boston Children's Hospital	RCV001788062	SCV002030078	uncertain significance	SUDDEN INFANT DEATH SYNDROME	2021-10-01	criteria provided, single submitter	research	We classify this variant as a variant of uncertain significance using ACMG/AMP criteria. As this variant is a deleterious splicing variant, we suspect this variant is favoring pathogenic.
Revvity Omics, Revvity	RCV000714068	SCV003825463	uncertain significance	not provided	2020-08-19	criteria provided, single submitter	clinical testing