Submissions for variant NM_001267550.2(TTN):c.105590G>A (p.Gly35197Asp)

gnomAD frequency: 0.00003  dbSNP: rs397517796

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040964	SCV000064655	uncertain significance	not specified	2012-02-23	criteria provided, single submitter	clinical testing	The Gly32629Asp variant (TTN) has not been previously reported but has bee ident ified by our laboratory in 1 individual with DCM who carried other likely diseas e causing DCM variants. This variant has also been identified in 1/6692 European American chromosomes from a broad population by the NHLBI Exome Sequencing Proj ect (http://evs.gs.washington.edu/EVS). Glycine (Gly) at position 32629 is highl y conserved in evolutionarily distant species, increasing the likelihood that a change would not be tolerated. Computational tools are mixed on the predicted im pact to the protein (AlignGVGD = benign, SIFT = pathogenic), though the accuracy of these tools is unknown. Additional information is needed to fully assess the Gly32629Asp variant.
Invitae	RCV001299722	SCV001488824	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 35197 of the TTN protein (p.Gly35197Asp). This variant is present in population databases (rs397517796, gnomAD 0.01%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 25163546). ClinVar contains an entry for this variant (Variation ID: 47695). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant is located in the M band of TTN (PMID: 25589632). Non-truncating variants in this region may be relevant for neuromuscular disorders, but have not been definitively shown to cause cardiomyopathy (PMID: 23975875). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV002483021	SCV002782851	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	2021-09-30	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000185124	SCV003826591	uncertain significance	not provided	2020-01-03	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000185124	SCV004229369	uncertain significance	not provided	2023-09-01	criteria provided, single submitter	clinical testing	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity (http://gnomad.broadinstitute.org). This variant has been seen where an alternate explanation for disease was also identified, suggesting this variant may not cause disease. Computational tools disagree on the variant's effect on normal protein function.
GeneDx	RCV000185124	SCV000237951	not provided	not provided	2013-03-01	no assertion provided	clinical testing	Missense variants in the TTN gene are considered 'unclassified' if they are not previously reported in the literature and do not have >1% frequency in the population to be considered a polymorphism. Research indicates that truncating mutations in the TTN gene are expected to account for approximately 25% of familial and 18% of sporadic idiopathic DCM; however, truncating variants in the TTN gene have been reported in approximately 3% of reported control alleles. There has been little investigation into non-truncating variants. (Herman D et al. Truncations of titin causing dilated cardiomyopathy. N Eng J Med 366:619-628, 2012) The variant is found in DCM panel(s).