Submissions for variant NM_001267550.2(TTN):c.86076dup (p.Ser28693fs)

dbSNP: rs1285329277

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000618269	SCV000736874	pathogenic	Cardiovascular phenotype	2023-01-24	criteria provided, single submitter	clinical testing	The c.58881dupA pathogenic mutation, located in coding exon 153 of the TTN gene, results from a duplication of A at nucleotide position 58881, causing a translational frameshift with a predicted alternate stop codon (p.S19628Ifs*2). 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 (also referred to as p.S19628Ifs*1 and p.Ser28693Ilefs*2) segregated with dilated cardiomyopathy in one large family and in two affected brothers from an unrelated family (Yoskovitz G et al. Am. J. Cardiol. 2012 Jun;11:1644-50; Franaszczyk M et al. PLoS One 2017 Jan;1:e0169007). 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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000623645	SCV000740482	pathogenic	not provided	2017-01-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000623645	SCV001167935	pathogenic	not provided	2021-10-21	criteria provided, single submitter	clinical testing	Reported in association with DCM in two families in the published literature; one family also harbored a second variant in the MYH6 gene (Yoskovitz et al., 2012; Franaszczyk et al., 2017); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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 titin, where the majority of truncating pathogenic variants associated with DCM have been reported (Herman et al., 2012).; This variant is associated with the following publications: (PMID: 22475360, 28045975, 30332462)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170546	SCV001333132	pathogenic	Cardiomyopathy	2018-03-16	criteria provided, single submitter	clinical testing
Invitae	RCV001855264	SCV002234036	pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-12-01	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser28693Ilefs*2) 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 present in population databases (no rsID available, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy (PMID: 22475360). It has also been observed to segregate with disease in related individuals. This variant is also known as c.58880insA (p.S19628IfsX1). ClinVar contains an entry for this variant (Variation ID: 519013). 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.