ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.51913_51916del (p.Lys17305fs)

dbSNP: rs747513278
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002001167 SCV002269774 likely pathogenic Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2022-04-18 criteria provided, single submitter clinical testing 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. This variant is located in the A band of TTN (PMID: 25589632). Truncating variants in this region are significantly overrepresented in patients affected with dilated cardiomyopathy (PMID: 25589632). Truncating variants in this region have also been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant is also known as c.46990_46993delAAGG (p.Lys15664Valfs*13). This premature translational stop signal has been observed in individual(s) with peripartum cardiomyopathy (PMID: 24558114). This variant is present in population databases (rs747513278, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Lys17305Valfs*13) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein.
Ambry Genetics RCV002443001 SCV002735590 pathogenic Cardiovascular phenotype 2020-11-06 criteria provided, single submitter clinical testing The c.24718_24721delAAGG pathogenic mutation, located in coding exon 100 of the TTN gene, results from a deletion of 4 nucleotides at nucleotide positions 24718 to 24721, causing a translational frameshift with a predicted alternate stop codon (p.K8240Vfs*13). This exon is located in the A-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 variant (referred to as c.46990_46993delAAGG, p.Lys15664Valfs*13) has been detected in a individual with peripartum cardiomyopathy and a family history of sudden cardiac death (van Spaendonck-Zwarts KY et al. Eur Heart J. 2014 Aug;35(32):2165-73). 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 A-band are the most common cause of dilated cardiomyopathy (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). TTN truncating variants encoded in constitutive exons (PSI >90%) have been found to be significantly associated with DCM regardless of their position in titin (Schafer S et al. Nat. Genet., 2017 01;49:46-53). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

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