Submissions for variant NM_001267550.2(TTN):c.64688dup (p.Gln21564fs)

dbSNP: rs774395395

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000385376	SCV000329561	pathogenic	not provided	2018-09-05	criteria provided, single submitter	clinical testing	The c.59765dupC pathogenic variant in the TTN gene has not been reported previously as a pathogenic variant or as a benign variant, to our knowledge. This variant causes a shift in reading frame starting at codon glutamine 19923, changing it to a serine, and creating a premature stop codon at position 5 of the new reading frame, denoted p.Gln19923SerfsX5. 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 truncating TTN variants have been reported in approximately 3% of control alleles (Herman et al., 2012). However, c.59765dupC is 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). Furthermore, the c.59765dupC variant is not observed in large population cohorts (Lek et al., 2016). In summary, c.59765dupC in the TTN gene is interpreted as a pathogenic variant.
Invitae	RCV000468454	SCV000542561	likely pathogenic	Dilated cardiomyopathy 1G	2016-08-30	criteria provided, single submitter	clinical testing	This sequence change inserts 1 nucleotide in exon 310 of the TTN mRNA (c.64688dupC), causing a frameshift at codon 21564. This creates a premature translational stop signal (p.Gln21564Serfs*5) and is expected to result in an absent or disrupted protein product. This variant is found in the A-band of this gene. While this particular variant has not been reported in the literature, truncating variants in the A-band of TTN are significantly overrepresented in patients with dilated cardiomyopathy and are considered to be likely pathogenic for the disease (PMID: 25589632). For these reasons, this variant has been classified as Likely Pathogenic.
Invitae	RCV001377254	SCV001574540	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-10-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln21564Serfs*5) 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 variant has not been reported in the literature in individuals affected with TTN-related conditions. ClinVar contains an entry for this variant (Variation ID: 279914). 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.
Revvity Omics, Revvity	RCV000385376	SCV002021469	likely pathogenic	not provided	2021-06-21	criteria provided, single submitter	clinical testing