Submissions for variant NM_001267550.2(TTN):c.97050dup (p.Glu32351fs)

gnomAD frequency: 0.00001  dbSNP: rs794729365

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000184363	SCV000236988	pathogenic	not provided	2022-08-24	criteria provided, single submitter	clinical testing	Previously identified in patients with DCM (Gigli et al., 2019; Ramchand et al., 2020); One patient tested at GeneDx with limb-girdle muscular dystrophy and no reported cardiomyopathy inherited this variant from a parent with cardiomyopathy and mild muscle weakness; segregation data from other families have demonstrated segregation with cardiomyopathy and reduced penetrance; 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 in large population cohorts (gnomAD); 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: 31931689, 31514951, 22335739)
Invitae	RCV000543494	SCV000642484	pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-12-09	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu32351Argfs*6) 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 dilated cardiomyopathy (PMID: 31514951; Invitae). ClinVar contains an entry for this variant (Variation ID: 202495). 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.
Eurofins Ntd Llc (ga)	RCV000184363	SCV000855473	likely pathogenic	not provided	2017-07-12	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002372131	SCV002668014	pathogenic	Cardiovascular phenotype	2021-03-02	criteria provided, single submitter	clinical testing	The c.69855dupA pathogenic mutation, located in coding exon 175 of the TTN gene, results from a duplication of A at nucleotide position 69855, causing a translational frameshift with a predicted alternate stop codon (p.E23286Rfs*6). 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 (also referred to as c.97050_97051insA and p.Glu32351Argfs*6) has been detected in individuals from dilated cardiomyopathy cohorts (Gigli M et al. J Am Coll Cardiol, 2019 09;74:1480-1490; Ramchand J et al. J Am Heart Assoc, 2020 01;9:e013346). 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). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Fulgent Genetics, Fulgent Genetics	RCV002500558	SCV002808958	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	2021-10-10	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003333041	SCV004041060	pathogenic	Dilated cardiomyopathy 1G	2023-01-22	criteria provided, single submitter	clinical testing
GenomeConnect, ClinGen	RCV001249379	SCV001423373	not provided	Primary dilated cardiomyopathy		no assertion provided	phenotyping only	Variant interpretted as Likely pathogenic and reported on 02-08-2015 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.