Submissions for variant NM_001267550.2(TTN):c.35678_35685delinsA (p.Thr11893fs)

dbSNP: rs2066169270

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV001328743	SCV001519929	uncertain significance	Early-onset myopathy with fatal cardiomyopathy	2020-07-01	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV003225967	SCV003922201	pathogenic	TTN-related myopathy	2023-05-02	criteria provided, single submitter	curation	The heterozygous p.Thr11893LysfsTer75 variant in TTN was identified by our study, in the compound heterozygous state with a pathogenic variant (ClinVar Variation ID: 226126), in two siblings with congenital myopathy. Familial exome analysis showed that this variant was in trans with a pathogenic variant (ClinVar Variation ID: 226126). The p.Thr11893LysfsTer75 variant in TTN has not been previously reported in individuals with autosomal recessive titin-associated myopathy. This variant is absent from population databases. This variant has also been reported in ClinVar (Variation ID: 1027852) and has been classified as a variant of uncertain significance by Baylor Genetics. The affected siblings identified by our study were compound heterozygotes who carried a reported pathogenic variant in trans, which increases the likelihood that the p.Thr11893LysfsTer75 variant is pathogenic. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 11893 and leads to a premature termination codon 75 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the TTN gene is an established disease mechanism in autosomal recessive titin-associated myopathy. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive titin-associated myopathy. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PM3 (Richards 2015).
GeneDx	RCV003232306	SCV003929775	pathogenic	not provided	2023-06-03	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a region of the TTN gene for which loss-of-function is a known mechanism of disease; Located in a region of TTN in which the majority of pathogenic variants have been reported in association with autosomal recessive titinopathies (Fernandez-Marmiesse et al., 2017; Chervinsky et al., 2018; Bryen, et al., 2020; Savarese et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 28040389, 29575618, 31660661, 32778822)