Submissions for variant NM_001267550.2(TTN):c.43600C>T (p.Gln14534Ter)

gnomAD frequency: 0.00001  dbSNP: rs727504499

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000155637	SCV000205345	likely pathogenic	Primary dilated cardiomyopathy	2015-07-30	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx	RCV004700482	SCV000236832	likely pathogenic	not provided	2024-04-29	criteria provided, single submitter	clinical testing	Has been observed in at least one individual from a cohort of patients with nonischemic dilated cardiomyopathy (PMID: 32998006); Located in a region of TTN within the I-band in which the majority of loss of function variants are significantly associated with autosomal dominant titinopathies. (PMID: 27625338, 27869827); This variant is associated with the following publications: (PMID: 27625338, 27869827, 32998006)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001216159	SCV001387939	pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2025-01-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln14534*) 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 (rs727504499, gnomAD 0.007%). This premature translational stop signal has been observed in individuals with dilated cardiomyopathy (internal data). ClinVar contains an entry for this variant (Variation ID: 178865). This variant is located in the I band of TTN (PMID: 25589632). Truncating variants in this region have been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875, internal data). Truncating variants in this region have also been identified in individuals affected with autosomal dominant dilated cardiomyopathy and/or cardio-related conditions (PMID: 27869827, 32964742, internal data). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002399552	SCV002707691	pathogenic	Cardiovascular phenotype	2024-12-13	criteria provided, single submitter	clinical testing	The p.Q5469* pathogenic mutation (also known as c.16405C>T), located in coding exon 63 of the TTN gene, results from a C to T substitution at nucleotide position 16405. This changes the amino acid from a glutamine to a stop codon within coding exon 63. This exon is located in the I-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 p.Gln14534Ter, c.43600C>T) was reported in individual(s) with features consistent with dilated cardiomyopathy (DCM) (Anderson JL et al. Am J Cardiol. 2020 12;137:97-102; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, 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 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 variant is interpreted as a disease-causing mutation.