Submissions for variant NM_001267550.2(TTN):c.103360del (p.Glu34454fs)

dbSNP: rs760768093

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000415229	SCV000492943	likely pathogenic	Limb-girdle muscular dystrophy; Muscular dystrophy; Waddling gait; Proximal lower limb amyotrophy; Decreased patellar reflex	2015-02-04	criteria provided, single submitter	clinical testing
Invitae	RCV000551103	SCV000639027	pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu34454Asnfs*3) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. This variant is present in population databases (rs760768093, gnomAD 0.004%). This premature translational stop signal has been observed in individuals with autosomal recessive distal myopathy, dilated cardiomyopathy, and/or left ventricular noncompaction cardiomyopathy (PMID: 28295036, 34540771, 35653365). ClinVar contains an entry for this variant (Variation ID: 374145). This variant is located in the M band of TTN (PMID: 25589632). Truncating variants in this region have been previously reported in individuals affected with autosomal recessive myopathy and muscular dystrophy (PMID: 18948003, 23975875, 24395473). Truncating variants in this region have also been identified in individuals affected with autosomal dominant dilated cardiomyopathy and/or cardio-related conditions (PMID: 27869827, 32964742, Invitae internal data). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV000788396	SCV000927486	likely pathogenic	not provided	2017-11-30	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001004984	SCV001164534	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2J	2018-12-03	criteria provided, single submitter	research	The heterozygous p.Glu34454AsnfsTer3 variant in TTN was identified by our study in one individual in the compound heterozygous state, with another pathogenic variant, in one individual with limb-girdle muscular dystrophy (LGMD). The presence of this variant in combination with a pathogenic variant and in an individual with limb-girdle muscular dystrophy (LGMD) increases the likelihood that the p.Glu34454AsnfsTer3 variant is pathogenic. This variant has been identified in 0.002170% (6/276492) of chromosomes in the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs760768093). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 34454, which is predicted to lead to a truncated or absent protein. Loss of function of the TTN gene is an established disease mechanism in autosomal recessive LGMD. In summary, this variant meets criteria to be classified as pathogenic forLGMD in an autosomal recessive manner based on the predicted impact of the variant and the presence of a pathogenic variant in an individual with LGMD. ACMG/AMP Criteria applied: PM2, PVS1, PM3 (Richards 2015).
GeneDx	RCV000788396	SCV001168556	pathogenic	not provided	2022-04-29	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 the M-line region of TTN, in which the majority of loss of function variants have been associated with autosomal recessive titinopathies (Carmignac et al., 2007); This variant is associated with the following publications: (PMID: 28295036, 32778822, 32528171, 34106991, 34540771)
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001196493	SCV001367101	pathogenic	Tibial muscular dystrophy	2019-02-20	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP5.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001262301	SCV001440115	likely pathogenic	Hypertrophic cardiomyopathy 9	2019-01-01	criteria provided, single submitter	clinical testing
Klaassen Lab, Charite University Medicine Berlin	RCV001814981	SCV002061916	likely pathogenic	Left ventricular noncompaction cardiomyopathy		criteria provided, single submitter	research
AiLife Diagnostics, AiLife Diagnostics	RCV000788396	SCV002502508	pathogenic	not provided	2021-10-12	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000788396	SCV002541906	uncertain significance	not provided	2021-11-19	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000788396	SCV002544128	likely pathogenic	not provided	2023-11-01	criteria provided, single submitter	clinical testing	TTN: PVS1:Strong, PM2, PS4:Moderate
Ambry Genetics	RCV002392941	SCV002668808	pathogenic	Cardiovascular phenotype	2023-05-05	criteria provided, single submitter	clinical testing	The c.76165delG pathogenic mutation, located in coding exon 185 of the TTN gene, results from a deletion of one nucleotide at nucleotide position 76165, causing a translational frameshift with a predicted alternate stop codon (p.E25389Nfs*3).This exon is located in the M-band region of the N2-B isoform of the titin protein and is constitutively expressed in TTN transcripts (percent spliced in or PSI 100%). This alteration (referred to as c.103360delG, p.Glu34454AsnfsTer3) has been detected in the compound heterozygous state with a TTN nonsense variant located in the M-band region in three individuals with distal skeletal myopathy from a Serbian cohort, and a common ancestor was suggested (Peri S et al. Eur. J. Hum. Genet., 2017 05;25:572-581). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. While truncating variants in TTN are present in 1-3% of the general population, truncating variants in the M-band have been reported in association with autosomal recessive titinopathies, primarily presenting with skeletal myopathy phenotypes (Ceyhan-Birsoy O et al. Neurology. 2013 Oct 1;81(14):1205-14; De Cid R et al. Neurology. 2015;85(24):2126-35). In addition, regardless of their position, TTN truncating variants encoded in constitutive exons (PSI >90%) have been found to be significantly associated with dilated cardiomyopathy (DCM), though truncating variants in the A-band are the most common cause of DCM (Herman DS et al. N. Engl. J. Med., 2012 Feb;366:619-28; Roberts AM et al. Sci Transl Med, 2015 Jan;7:270ra6; Schafer S et al. Nat. Genet., 2017 01;49:46-53). Based on the majority of available evidence to date, this variant is pathogenic in association with autosomal recessive titinopathy; however, the clinical significance of this alteration with respect to cardiomyopathy remains unclear.
Center for Human Genetics, University of Leuven	RCV003237346	SCV002817413	likely pathogenic	Primary dilated cardiomyopathy	2022-12-31	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000788396	SCV003815888	likely pathogenic	not provided	2021-12-07	criteria provided, single submitter	clinical testing
3billion	RCV001004984	SCV003841820	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-02-23	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). This variant was 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 at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000374145). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.