ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.103360del (p.Glu34454fs) (rs760768093)

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Total submissions: 7
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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; Limb-girdle muscular dystrophy, type 2J 2020-10-05 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu34454Asnfs*3) in the TTN gene. It is expected to result in a disrupted protein product. This variant is present in population databases (rs760768093, ExAC 0.003%). This variant has been observed in individual(s) with autosomal recessive distal myopathy (PMID: 28295036). 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), but have not been definitively shown to cause cardiomyopathy (PMID: 25589632). 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 Institute Rare Disease Group, Broad Institute RCV001004984 SCV001164534 pathogenic 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 2018-10-29 criteria provided, single submitter clinical testing The c.98437delG variant (reported as c.103360delG due to the use of alternate nomenclature) in the TTN gene has been reported in three patients with distal myopathy who also harbored a nonsense variant in the TTN gene in trans (Peric et al., 2017). This variant causes a shift in reading frame starting at codon glutamic acid 32813, changing it to an asparagine, and creating a premature stop codon at position 3 of the new reading frame, denoted p.Glu32813AsnfsX3. This pathogenic variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other frameshift variants in the TTN gene have been reported in Human Gene Mutation Database in association with DCM (Stenson et al., 2014). However, c.98437delG is not located in the A-band region of titin, where the majority of truncating pathogenic variants associated with DCM have been reported (Herman et al., 2012). Other truncating variants in the M-band of titin, where this variant occurs, have been reported in association with an autosomal recessive early-onset myopathy with cardiomyopathy (Carmignac et al., 2007), and heterozygous parents were reportedly healthy. Furthermore, other nonsense and frameshift TTN variants have been reported in approximately 3% of control alleles (Herman et al., 2012). Finally, the c.98437delG variant has been observed in 7/280032 (0.0025%) alleles from individuals of multiple ethnic backgrounds in large population cohorts (Lek et al., 2016). In summary, c.98437delG in the TTN gene is interpreted as a pathogenic variant.
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 Familial hypertrophic cardiomyopathy 9 2019-01-01 criteria provided, single submitter clinical testing

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