Submissions for variant NM_001267550.2(TTN):c.98994del (p.Lys32998fs)

dbSNP: rs727504535

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000155686	SCV000205396	likely pathogenic	Primary dilated cardiomyopathy	2019-01-18	criteria provided, single submitter	clinical testing	The p.Lys30430AsnfsX63 variant in TTN has been identified in 1 individual with DCM (LMM data) and was idnetified in 1/109666 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frameshift variant is predicted to alter the protein’s amino acid sequence beginning at position 30430 and lead to a premature termination codon 63 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Frameshift and other truncating variants in TTN are strongly associated with DCM if they impact the exons encoding for the A-band (Herman 2012, Pugh 2014) and/or are located in an exon that is highly expressed in the heart (Roberts 2015). The p.Lys30430AsnfsX63 variant is located in A-band in a highly expressed exon. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant DCM. ACMG/AMP Criteria applied: PVS1, PM2.
GeneDx	RCV000184328	SCV000236953	pathogenic	not provided	2023-01-30	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Located in the A-band region of TTN in which the majority of loss of function variants have been associated with autosomal dominant titinopathies (Herman et al., 2012); This variant is associated with the following publications: (PMID: 33500567, 22335739, 35605965)
Invitae	RCV000702876	SCV000831748	pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys32998Asnfs*63) 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 clinical features of autosomal dominant TTN-related conditions and/or clinical features of autosomal recessive congenital myopathy (PMID: 33500567, 35605965). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 178913). 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). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001804868	SCV002051145	likely pathogenic	Primary familial dilated cardiomyopathy	2021-12-15	criteria provided, single submitter	clinical testing	Variant summary: TTN c.91290delA (p.Lys30430AsnfsX63) 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. The variant occurs in the A-band region of titin within a constitutively expressed exon. The variant allele was found at a frequency of 4.2e-06 in 240770 control chromosomes (gnomAD). To our knowledge, no occurrence of c.91290delA in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submitters have assessed this variant since 2014: two have classified it as likely pathogenic, and one as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Ambry Genetics	RCV002372018	SCV002667114	pathogenic	Cardiovascular phenotype	2021-07-08	criteria provided, single submitter	clinical testing	The c.71799delA pathogenic mutation, located in coding exon 181 of the TTN gene, results from a deletion of one nucleotide at nucleotide position 71799, causing a translational frameshift with a predicted alternate stop codon (p.K23933Nfs*63). This variant has been detected in individuals with dilated cardiomyopathy (Ambry internal data). 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 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.
Athena Diagnostics Inc	RCV000184328	SCV004229413	uncertain significance	not provided	2023-01-13	criteria provided, single submitter	clinical testing	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity (http://gnomad.broadinstitute.org). This variant is predicted to result in premature termination and the loss of a functional protein in three main isoforms (major cardiac long isoform: NM_001256850.1, major skeletal muscle long isoform: NM_133378.4, and the inferred complete isoform: NM_001267550.1). This variant is in the TTN A-band. Premature termination variants that occur in this region are enriched in cardiomyopathy patients compared to the general population (PMID: 31849696), while their significance for muscular dystrophy is uncertain. Premature termination variants in the TTN gene have also been found in healthy individuals (PMID: 25589632).