Submissions for variant NM_001267550.2(TTN):c.38661_38665del (p.Lys12887fs)

dbSNP: rs1553775212

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV003225935	SCV003922097	pathogenic	TTN-related myopathy	2023-05-01	criteria provided, single submitter	curation	The heterozygous p.Lys12887AsnfsTer6 variant in TTN was identified by our study, in the compound heterozygous state with a pathogenic variant (ClinVar Variation ID: 1027852), in two siblings with congenital myopathy. Familial exome analysis showed that this variant was in trans with a pathogenic variant (ClinVar Variation ID: 1027852). The p.Lys12887AsnfsTer6 variant in TTN has been previously reported in one individual with autosomal recessive titin-associated myopathy (PMID: 28040389), but has been identified in 0.0008% (2/264690) of chromosomes in TopMed. Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 226126) and has been classified as likely pathogenic by NeuroMeGen,Hospital Clinico Santiago de Compostela. The one affected individual previously reported was homozygous for the variant (PMID: 28040389), which increases the likelihood that the p.Lys12887AsnfsTer6 variant is pathogenic. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 12887 and leads to a premature termination codon 6 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_Supporting (Richards 2015).
GeneDx	RCV004719763	SCV005325971	pathogenic	not provided	2023-08-29	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a 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); Identified in patients with congenital myopathy who have additional TTN variants (Natera-de Benito et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 35628876, 32778822, 28040389, 29575618, 31660661, 33333461)
3billion	RCV005252818	SCV005905161	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-08-04	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported to be associated with TTN related disorder (ClinVar ID: VCV000226126). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
NeuroMeGen, Hospital Clinico Santiago de Compostela	RCV000203600	SCV000258980	likely pathogenic	CAP-congenital myopathy with arthrogryposis multiplex congenita without heart involvement		no assertion criteria provided	clinical testing