ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.107889del (p.Lys35963fs) (rs281864930)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000184369 SCV000229485 pathogenic not provided 2018-08-14 criteria provided, single submitter clinical testing
GeneDx RCV000184369 SCV000236994 pathogenic not provided 2018-08-22 criteria provided, single submitter clinical testing The c.102966delA pathogenic variant in the M-band region of the TTN gene (also referred to as c.100185delA, c.107889delA, and g.293376delA, due to alternate transcript nomenclature) has been previously reported in multiple individuals with TTN-related disorders who were either homozygous, compound heterozgyous with a second variant on the opposite TTN allele (in trans), or heterozygous for this variant (Hackman et al., 2008; Ceyhan-Birsoy et al., 2013; Evila et al., 2014; Evila et al., 2016). This variant (reported as c.100185delA) was identified in the compound heterozygous state with a pathogenic nonsense variant in an individual with suspected muscular dystrophy who was noted to have moderately elevated serum creatine phosphokinase levels and findings on muscle biopsy consistent with centronuclear myopathy (Ceyhan-Birsoy et al., 2013). The c.102966delA variant (reported as c.107889delA) was also identified in two patients with severe tibial muscular dystrophy (TMD), one patient was homozygous for this variant while the other patient harbored a second TTN frameshift variant in trans; the heterozygous parents of these individuals were asymptomatic (Evila et al., 2014). Two patients with distal titinopathy also harbored this variant, one patient harbored an additional frameshift TTN variant while the other patient had no second variant identified (Evila et al., 2016). This variant has also been reported (as g.293378delA) in the heterozygous state in individuals from two Spanish families with tibial muscular dystrophy (TMD) (Hackman et al., 2008).Considering cardiac phenotypes, Campuzano et al. (2015) identified this variant (reported as c.100185delA) in both dilated cardiomyopathy (DCM) and sudden unexplained death patient cohorts, but specific clinical details and segregation data were not provided. The c.102966delA variant has been identified in conjunction with a second likely pathogenic or pathogenic TTN variant in other unrelated individuals referred for genetic testing for neuromuscular disorders at GeneDx. This variant causes a shift in reading frame starting at codon lysine 34322, changing it to an asparagine, and creating a premature stop codon at position 9 of the new reading frame, denoted p.Lys34322AsnfsX9. The c.102966delA variant is predicted to cause loss of normal protein function through protein truncation, as the last 29 amino acids of the titin protein are lost and replaced with 8 incorrect amino acids. Finally, this variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016).In summary, c.102966delA in the TTN gene is interpreted as a pathogenic variant.
Broad Institute Rare Disease Group, Broad Institute RCV001004988 SCV001164539 pathogenic Limb-girdle muscular dystrophy, type 2J 2018-12-03 criteria provided, single submitter research The heterozygous p.Lys35963AsnfsTer9 variant in TTN was identified by our study in the compound heterozygous state with a 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 LGMD increases the likelihood that the p.Lys35963AsnfsTer9 variant is pathogenic. This variant has been identified in 0.001083% (3/277072) of chromosomes in the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs281864929). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 35963 and leads to a premature termination codon 9 amino acids downstream. This termination codon occurs within the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. However, the truncated protein region in the last exon includes the A-band (PMID: 26777568). This variant has also been reported in ClinVar (Variation ID: 38439). Loss of function of the TTN gene is an established disease mechanism in autosomal recessive LGMD. In summary, the p.Lys35963AsnfsTer9 variant is pathogenic based off of our findings, multiple reports in ClinVar, and the literature. ACMG/AMP Criteria applied: PM2, PVS1_Strong, PM3, PM1 (Richards 2015).
Invitae RCV001216397 SCV001388193 pathogenic Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2019-05-21 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the TTN gene (p.Lys35963Asnfs*9). 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 (rs281864930, ExAC 0.002%). This variant has been observed in individuals with autosomal recessive centronuclear myopathy or tibial muscular dystrophy (PMID: 24395473, 26627873, 23975875). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant has also been observed as heterozygous in individuals affected with dilated cardiomyopathy and sudden death (PMID: 26516846). This variant is also known as p.K33395NfsX9 in the literature. This variant has been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333). 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), but have not been definitively shown to cause cardiomyopathy (PMID: 25589632). For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics Inc RCV000184369 SCV001474957 pathogenic not provided 2020-03-13 criteria provided, single submitter clinical testing The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity.
GeneReviews RCV000031995 SCV000054699 pathologic Tibial muscular dystrophy 2012-08-23 no assertion criteria provided curation Converted during submission to Pathogenic.
GenomeConnect, ClinGen RCV000844994 SCV000986824 not provided Myopathy, myofibrillar, 9, with early respiratory failure no assertion provided phenotyping only Variant interpretted as pathogenic and reported on 01/12/2018 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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