Submissions for variant NM_001267550.2(TTN):c.66160G>T (p.Asp22054Tyr)

dbSNP: rs1057523177

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000439903	SCV000530975	uncertain significance	not provided	2018-06-26	criteria provided, single submitter	clinical testing	The D19486Y variant in the TTN gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The D19486Y variant is not observed in large population cohorts (Lek et al., 2016). The D19486Y variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved. However, in silico analysis predicts this variant is probably damaging to the protein structure/function. As an alternate mechanism, this sequence change is also predicted to destroy the natural splice donor site in intron 263, which is expected to cause abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. We interpret D19486Y as a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV005209505	SCV005850948	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-10-30	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 22054 of the TTN protein (p.Asp22054Tyr). This variant also falls at the last nucleotide of exon 314, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This variant has not been observed in the literature in individuals with autosomal recessive TTN-related conditions. This variant has been reported in individual(s) with dilated cardiomyopathy (internal data); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 388627). 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 A band of TTN (PMID: 25589632). Variants in this region may be relevant for cardiac or neuromuscular disorders (PMID: 25589632, 23975875). 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.