Submissions for variant NM_001267550.2(TTN):c.60734G>A (p.Arg20245Gln)

gnomAD frequency: 0.00016  dbSNP: rs575837567

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000231887	SCV000286760	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2016-10-25	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with glutamine at codon 20245 of the TTN protein (p.Arg20245Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs575837567, ExAC 0.02%) but has not been reported in the literature. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
Eurofins Ntd Llc (ga)	RCV000313555	SCV000333527	uncertain significance	not provided	2017-01-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002321866	SCV002607143	uncertain significance	Cardiovascular phenotype	2019-03-26	criteria provided, single submitter	clinical testing	The p.R11180Q variant (also known as c.33539G>A), located in coding exon 131 of the TTN gene, results from a G to A substitution at nucleotide position 33539. The arginine at codon 11180 is replaced by glutamine, an amino acid with highly similar properties. This variant was identified in a population-based cohort study of QT interval variation; however clinical details were not provided (Kapoor A et al. Sci Rep, 2016;6:28356 (reported as p.R20245Q)). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000313555	SCV003819706	uncertain significance	not provided	2020-01-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488484	SCV004241828	uncertain significance	not specified	2023-12-04	criteria provided, single submitter	clinical testing	Variant summary: TTN c.53030G>A (p.Arg17677Gln) results in a conservative amino acid change located in the A band region of the encoded protein sequence. Two of four 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 247704 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in TTN causing Dilated Cardiomyopathy (4.8e-05 vs 0.00039), allowing no conclusion about variant significance. c.53030G>A has been reported in the literature in a population-based cohort study of QT interval variation; however clinical details were not providedy (Kapoor_2016). These report(s) do 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: 27321809). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.