Submissions for variant NM_001267550.2(TTN):c.101378A>T (p.Asp33793Val)

gnomAD frequency: 0.00009  dbSNP: rs200675195

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000220026	SCV000272822	uncertain significance	not specified	2015-03-05	criteria provided, single submitter	clinical testing	The p.Asp31225Val variant in TTN has not been previously reported in individuals with cardiomyopathy, but has been identified in 14/66724 of European American c hromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute .org; dbSNP rs200675195). Computational prediction tools and conservation analys is suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical signi ficance of the p.Asp31225Val variant is uncertain.
Invitae	RCV000466841	SCV000542784	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-11-23	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000730725	SCV000858487	uncertain significance	not provided	2017-12-05	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769858	SCV000901284	uncertain significance	Cardiomyopathy	2017-04-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000730725	SCV001778434	likely benign	not provided	2019-09-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002381750	SCV002674471	uncertain significance	Cardiovascular phenotype	2019-12-04	criteria provided, single submitter	clinical testing	The p.D24728V variant (also known as c.74183A>T), located in coding exon 185 of the TTN gene, results from an A to T substitution at nucleotide position 74183. The aspartic acid at codon 24728 is replaced by valine, an amino acid with highly dissimilar 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 alteration remains unclear.
Revvity Omics, Revvity	RCV000730725	SCV003819859	uncertain significance	not provided	2023-02-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000220026	SCV004241005	uncertain significance	not specified	2023-12-12	criteria provided, single submitter	clinical testing	Variant summary: TTN c.93674A>T (p.Asp31225Val) results in a non-conservative amino acid change located in the M-band domain of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.8e-05 in 249074 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in TTN causing Dilated Cardiomyopathy (8.8e-05 vs 0.00039), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.93674A>T in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as uncertain significance (n=6) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.