ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.51436C>T (p.Gln17146Ter)

dbSNP: rs906494713
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego RCV000852521 SCV000995219 pathogenic Primary dilated cardiomyopathy 2018-01-05 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001216730 SCV001388541 likely pathogenic Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2023-10-28 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln17146*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 691694). 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). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001328329 SCV001519404 likely pathogenic Primary familial dilated cardiomyopathy 2021-03-11 criteria provided, single submitter clinical testing Variant summary: TTN c.43732C>T (p.Gln14578X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 3.9e-06 in 256094 control chromosomes (gnomAD and publication data). c.43732C>T has been reported in the literature in one individual affected with Dilated Cardiomyopathy (Walsh_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic and likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Ambry Genetics RCV002442788 SCV002732881 likely pathogenic Cardiovascular phenotype 2023-10-16 criteria provided, single submitter clinical testing The p.Q8081* variant (also known as c.24241C>T), located in coding exon 98 of the TTN gene, results from a C to T substitution at nucleotide position 24241. This changes the amino acid from a glutamine to a stop codon within coding exon 98. 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 NM_001267550:c.51436C>T, p.Q17146X) was reported in one individual from a dilated cardiomyopathy (DCM) genetic testing cohort; however, clinical details were not provided (Walsh R et al. Genet. Med., 2017 02;19:192-203). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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). As such, this alteration is classified as likely pathogenic.

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