Submissions for variant NM_001267550.2(TTN):c.31594G>A (p.Val10532Ile)

gnomAD frequency: 0.00003  dbSNP: rs763955552

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000727167	SCV000236822	uncertain significance	not provided	2017-10-20	criteria provided, single submitter	clinical testing	The V10215I (c.30643 G>A) variant in the TTN gene has not been reported as pathogenic or benign to ourknowledge. However, this variant is reported in ClinVar as a variant of uncertain significance by another clinicallaboratory (SCV000543034.1; Landrum et al., 2016). The V10215I (c.30643 G>A) variant results in a conservativeamino acid substitution, which is not likely to impact secondary protein structure as these residues share similarproperties. However, this substitution is located within the last nucleotide of exon 117 that is conserved acrossspecies, and in silico analysis predicts this variant destroys the natural splice donor site in intron 117, which mayresult in aberrant gene splicing. However, in the absence of functional mRNA studies, the physiological consequenceof this variant cannot be precisely determined. Furthermore, V10215I (c.30643 G>A) resides in the I-band region,whereas the majority of pathogenic variants in the TTN gene that are associated with DCM are truncating variants inthe A-band region (Herman et al., 2012). Finally, this variant is observed in 23/123434 (0.02%) of alleles fromEuropean (non-Finnish) ancestry in large population cohorts (Lek et al., 2016).
Invitae	RCV000472469	SCV000543034	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-20	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 10532 of the TTN protein (p.Val10532Ile). This variant also falls at the last nucleotide of exon 119, which is part of the consensus splice site for this exon. This variant is present in population databases (rs763955552, gnomAD 0.02%). This missense change has been observed in individual(s) with noncompaction cardiomyopathy (PMID: 29447731). ClinVar contains an entry for this variant (Variation ID: 202358). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant is located in the I band of TTN (PMID: 25589632). Non-truncating variants in this region may be clinically relevant, but have not been definitively shown to cause cardiomyopathy or neuromuscular disease (PMID: 27493940, 32778822). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Eurofins Ntd Llc (ga)	RCV000727167	SCV000706310	uncertain significance	not provided	2017-12-05	criteria provided, single submitter	clinical testing
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV000853443	SCV000996354	uncertain significance	Primary dilated cardiomyopathy	2017-09-12	criteria provided, single submitter	research	The TTN Val10532Ile variant has not been previously reported in any cardiac condition. We identified this variant in a patient with mild left ventricular dilation and conduction system disease. The variant was also found to segregate to the proband's sibling who has DCM and conduction system disease. A second variant was also identified in this proband and segregated to the sibling. The variant is present in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), at an allele frequency >0.00008 which is higher then expected for an inherited heart condition. Computational tool PolyPhen2 predicts the variant to be "possibly-damaging", however MutationTaster predicts this variant to be a "polymorphism". In summary the evidence for the pathogenicity of this variant is lacking, therefore we classify TTN Val10532Ile as a variant of 'uncertain significance'.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002222431	SCV002500183	uncertain significance	not specified	2022-03-07	criteria provided, single submitter	clinical testing	Variant summary: TTN c.27862G>A (p.Val9288Ile) results in a conservative amino acid change located in the I-band region of the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. As the variant alters a conserved nucleotide located at the last position of the exon adjacent to the intronic splice donor site, several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00011 in 238548 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in TTN causing Dilated Cardiomyopathy (0.00011 vs 0.00039), allowing no conclusion about variant significance. c.27862G>A has been reported in the literature as a VUS in a cohort of individuals with noncompaction cardiomyopathy (NCCM) (example, van Wanning_2018). 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. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV002492833	SCV002797048	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J; Tibial muscular dystrophy; Myopathy, myofibrillar, 9, with early respiratory failure; Early-onset myopathy with fatal cardiomyopathy; Hypertrophic cardiomyopathy 9	2021-11-02	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000727167	SCV003827368	uncertain significance	not provided	2023-03-30	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000727167	SCV004225887	uncertain significance	not provided	2022-09-06	criteria provided, single submitter	clinical testing	BP1, PVS1_moderate