Submissions for variant NM_001267550.2(TTN):c.75138_75141del (p.Lys25046fs)

dbSNP: rs794729340

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000184330	SCV000236955	likely pathogenic	not provided	2017-03-06	criteria provided, single submitter	clinical testing	Although the c.70215_70218delAGAA mutation in the TTN gene has not been reported to our knowledge, this mutation causes a shift in reading frame starting at codon Lysine 23405, changing it to an Asparagine, and creating a premature stop codon at position 8 of the new reading frame, denoted p.Lys23405AsnfsX8. This mutation 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 D et al., 2012). However, c.70215_70218delAGAA is located in the A-band region of titin, where the majority of truncating mutations associated with DCM have been reported (Herman D et al., 2012). In summary, c.70215_70218delAGAA in the TTN gene is interpreted as a disease-causing mutation.
Baylor Genetics	RCV000680140	SCV000807584	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	2017-09-01	criteria provided, single submitter	clinical testing	This frameshift variant is categorized as deleterious according to ACMG guidelines (PMID:18414213) and was found once in our laboratory In trans with a missense variant (W7053C) in an 8-year-old male with congenital myopathy, hypotonia, hyperextensibility, scapular winging, weakness, joint laxity, ankle contractures, type I fiber predominance on muscle biopsy, family history of a brother with a similar phenotype (also compound heterozygous)
Invitae	RCV001203442	SCV001374608	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-09-25	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of autosomal recessive centronuclear myopathy and/or limb-girdle muscular dystrophy (PMID: 33226272; Invitae). This variant is also known as c.67434_67437del (p.K22477fs). ClinVar contains an entry for this variant (Variation ID: 202467). 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. This sequence change creates a premature translational stop signal (p.Lys25046Asnfs*8) 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 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).
Ambry Genetics	RCV002336476	SCV002634641	likely pathogenic	Cardiovascular phenotype	2023-07-03	criteria provided, single submitter	clinical testing	The c.47943_47946delAGAA variant, located in coding exon 153 of the TTN gene, results from a deletion of 4 nucleotides at nucleotide positions 47943 to 47946, causing a translational frameshift with a predicted alternate stop codon (p.K15981Nfs*8). 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 (referred to as NM_133378.4:c.67434_67437del, p.K22477fs) was detected in an individual referred for clinical exome sequencing whose phenotype was indicated to be limb-girdle muscular dystrophy and pathology was indicated as cardiomyopathy (CM); however, details were limited (Connell PS et al. Circ Genom Precis Med, 2021 02;14:e003131). 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.