ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.3913G>T (p.Gly1305Trp)

gnomAD frequency: 0.00003  dbSNP: rs199889888
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000152509 SCV000201685 uncertain significance not specified 2013-11-11 criteria provided, single submitter clinical testing The Gly1305Trp variant in TTN has not been previously reported in individuals wi th cardiomyopathy or in large population studies. Computational analyses (bioche mical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) sugge st that the Gly1305Trp variant may impact the protein, though this information i s not predictive enough to determine pathogenicity. Additional information is ne eded to fully assess the clinical significance of the Gly1305Trp variant
Eurofins Ntd Llc (ga) RCV000725635 SCV000701054 uncertain significance not provided 2016-10-19 criteria provided, single submitter clinical testing
GeneDx RCV000725635 SCV000728635 likely benign not provided 2019-07-22 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000643675 SCV000765362 uncertain significance Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2018-01-03 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV000770150 SCV000901576 uncertain significance Cardiomyopathy 2016-07-21 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000152509 SCV002014880 uncertain significance not specified 2023-08-03 criteria provided, single submitter clinical testing Variant summary: TTN c.3913G>T (p.Gly1305Trp) results in a non-conservative amino acid change located in the near Z-disk 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 6.4e-05 in 250082 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in TTN causing Dilated Cardiomyopathy (6.4e-05 vs 0.00039), allowing no conclusion about variant significance. c.3913G>T has been reported in the literature in at least one individual affected with familial atrial fibrillation (Maltese_2019). 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 has been ascertained in the context of this evaluation (PMID: 31539150). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=5) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics RCV002345483 SCV002620769 uncertain significance Cardiovascular phenotype 2020-05-29 criteria provided, single submitter clinical testing The p.G1259W variant (also known as c.3775G>T), located in coding exon 21 of the TTN gene, results from a G to T substitution at nucleotide position 3775. The glycine at codon 1259 is replaced by tryptophan, 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 deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity RCV000725635 SCV003822309 uncertain significance not provided 2020-09-14 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000725635 SCV004148213 uncertain significance not provided 2022-06-01 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000725635 SCV004225940 uncertain significance not provided 2022-02-10 criteria provided, single submitter clinical testing PP3

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