Submissions for variant NM_001267550.2(TTN):c.75633_75636dup (p.Val25213fs)

dbSNP: rs1553603036

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000624251	SCV000741113	likely pathogenic	Inborn genetic diseases	2018-01-04	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: UNCERTAIN: Alteration(s) of Uncertain Clinical Significance Detected
Invitae	RCV000801700	SCV000941492	pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Val25213Cysfs*25) 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 individuals with clinical features of dilated cardiomyopathy (PMID: 27532257; Invitae). ClinVar contains an entry for this variant (Variation ID: 520818). 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.
Revvity Omics, Revvity	RCV001783115	SCV002020329	likely pathogenic	not provided	2019-10-24	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV001783115	SCV002502745	likely pathogenic	not provided	2021-09-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002334037	SCV002639292	likely pathogenic	Cardiovascular phenotype	2022-05-24	criteria provided, single submitter	clinical testing	The c.48438_48441dupTGTT variant, located in coding exon 153 of the TTN gene, results from a duplication of TGTT at nucleotide position 48438, causing a translational frameshift with a predicted alternate stop codon (p.V16148Cfs*25). 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 was identified in one individual with dilated cardiomyopathy; however, clinical details were limited (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.
Fulgent Genetics, Fulgent Genetics	RCV002483743	SCV002785363	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J; Tibial muscular dystrophy; Myopathy, myofibrillar, 9, with early respiratory failure; Early-onset myopathy with fatal cardiomyopathy; Hypertrophic cardiomyopathy 9	2021-10-09	criteria provided, single submitter	clinical testing
GeneDx	RCV001783115	SCV004021720	likely pathogenic	not provided	2023-01-23	criteria provided, single submitter	clinical testing	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); Identified in a patient with DCM in published literature (Walsh et al., 2017); 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27532257, 22335739)