Submissions for variant NM_001267550.2(TTN):c.93130G>A (p.Gly31044Ser)

gnomAD frequency: 0.00005  dbSNP: rs750213547

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000216521	SCV000237774	uncertain significance	not specified	2013-03-13	criteria provided, single submitter	clinical testing	Missense variants in the TTN gene are considered 'unclassified' if they are not previously reported in the literature and do not have >1% frequency in the population to be considered a polymorphism. Research indicates that truncating mutations in the TTN gene are expected to account for approximately 25% of familial and 18% of sporadic idiopathic DCM; however, truncating variants in the TTN gene have been reported in approximately 3% of reported control alleles. There has been little investigation into non-truncating variants. (Herman D et al. Truncations of titin causing dilated cardiomyopathy. N Eng J Med 366:619-628, 2012) The variant is found in DCM panel(s).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000216521	SCV000272798	uncertain significance	not specified	2015-11-24	criteria provided, single submitter	clinical testing	The p.Gly28476Ser variant in TTN has not been previously reported in individuals with DCM, but has been identified in 5/66610 European and 2/16510 South Asian c hromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute .org). Computational prediction tools and conservation analysis suggest that thi s variant may impact the protein. Additionally, splicing tools strongly suggest this variant may lead to the creation of a novel 3' splice site. However, these tools are not predictive enough to determine pathogenicity. In summary, the clin ical significance of the p.Gly28476Ser variant is uncertain.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000216521	SCV002556031	uncertain significance	not specified	2022-06-20	criteria provided, single submitter	clinical testing	Variant summary: TTN c.85426G>A (p.Gly28476Ser) results in a non-conservative amino acid change located in the A-band region of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 248422 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in TTN causing Dilated Cardiomyopathy (4.8e-05 vs 0.00039), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.85426G>A in individuals affected with Dilated Cardiomyopathy, Limb-Girdle Muscular Dystrophy, or other TTN-related disorders and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV002372134	SCV002667615	uncertain significance	Cardiovascular phenotype	2020-01-07	criteria provided, single submitter	clinical testing	The p.G21979S variant (also known as c.65935G>A), located in coding exon 166 of the TTN gene, results from a G to A substitution at nucleotide position 65935. The glycine at codon 21979 is replaced by serine, an amino acid with 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 alteration remains unclear.
Revvity Omics, Revvity	RCV003137744	SCV003824239	uncertain significance	not provided	2021-07-21	criteria provided, single submitter	clinical testing