Submissions for variant NM_001267550.2(TTN):c.63793G>A (p.Asp21265Asn)

gnomAD frequency: 0.00003  dbSNP: rs794729474

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000184710	SCV000237407	uncertain significance	not provided	2018-05-04	criteria provided, single submitter	clinical testing	The D19624N (c.58870 G>A) variant of uncertain significance in the TTN gene has previously been reported by Lopes et al. (2013) as a rare variant in an individual with hypertrophic cardiomyopathy (reported as D12200N due to the use of alternative nomenclature). This variant has also been identified in other unrelated individuals referred for cardiomyopathy genetic testing at GeneDx, and was found to segregate with DCM in one affected relative. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). At the protein level, the D19624N variant results in a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. At the mRNA level, the c.58870 G>A variant occurs at the last nucleotide position of exon 256, which is conserved across species and is often involved in splicing. In silico splicing models predict that this variant may affect normal gene splicing by destroying the natural splice donor site for intron 256. However, in the absence of functional mRNA studies, the physiological consequence of this variant cannot be determined. In addition, other truncating TTN variants have been reported in approximately 3% of control alleles (Herman et al., 2012). Nevertheless, D19624N (c.58870 G>A) 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). Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000460249	SCV000542328	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-12-20	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 21265 of the TTN protein (p.Asp21265Asn). This variant also falls at the last nucleotide of exon 306, which is part of the consensus splice site for this exon. This variant is present in population databases (rs794729474, gnomAD 0.003%). This missense change has been observed in individuals with dilated cardiomyopathy and/or myopathy (PMID: 31561939, 31983221; internal data). ClinVar contains an entry for this variant (Variation ID: 202779). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant is located in the A band of TTN (PMID: 25589632). Variants in this region may be relevant for cardiac or neuromuscular disorders (PMID: 25589632, 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.
Baylor Genetics	RCV001329653	SCV001521148	uncertain significance	Tibial muscular dystrophy	2019-06-12	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Ambry Genetics	RCV002453683	SCV002617638	likely benign	Cardiovascular phenotype	2020-09-23	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Fulgent Genetics, Fulgent Genetics	RCV002485246	SCV002792066	uncertain significance	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	2021-09-18	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003486751	SCV004240055	likely pathogenic	Cardiomyopathy	2023-05-16	criteria provided, single submitter	clinical testing
Human Development and Health, University of Southampton	RCV000184710	SCV002106376	not provided	not provided		no assertion provided	in vitro