Submissions for variant NM_001267550.2(TTN):c.29621_29624del (p.Glu9874fs)

dbSNP: rs777924443

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000785925	SCV000924504	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2J	2018-06-15	criteria provided, single submitter	research	The heterozygous p.Glu9874GlyfsTer28 variant was identified in the compound heterozygous state, with another pathogenic variant, by our study in one individual with limb-girdle muscular dystrophy. This variant was absent from large population studies. Loss of function of the TTN gene is an established disease mechanism in autosomal recessive limb-girdle muscular dystrophy, and this is a loss of function variant. In summary, this variant is pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001869173	SCV002125067	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-03-01	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu9874Glyfs*28) 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 (rs777924443, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with clinical features of autosomal recessive TTN-related conditions (PMID: 30365001, 32528171, 32778822). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 635051). This variant is located in the I band of TTN (PMID: 25589632). Truncating variants in this region have been shown to be highly prevalent in the general population and unaffected individuals (PMID: 26701604, 22335739). However, truncating variants in this region have also been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Klaassen Lab, Charite University Medicine Berlin	RCV002067387	SCV002495746	likely pathogenic	Primary dilated cardiomyopathy; Myocarditis		criteria provided, single submitter	research
GeneDx	RCV002508254	SCV002818013	uncertain significance	not provided	2022-12-29	criteria provided, single submitter	clinical testing	Reported in a patient with limb-girdle weakness in published literature (Topf et al., 2020); however, clinical and segregation data are limited; Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a region of the gene for which loss-of-function is not a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Reported in ClinVar but additional evidence is not available (ClinVar Variant ID#635051); Located in a region of TTN within the I-band in which the majority of loss of function variants are significantly associated with autosomal dominant titinopathies (Deo et al., 2016; Schafer et al., 2017); This variant is associated with the following publications: (PMID: 32778822, 32528171, 27625338, 27869827, 35177841, 34213952, 30365001)
3billion	RCV000785925	SCV003842097	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: <0.001%). 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: VCV000635051). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.