Submissions for variant NM_001267550.2(TTN):c.97198C>A (p.Pro32400Thr)

gnomAD frequency: 0.00011  dbSNP: rs373876117

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000222441	SCV000272811	uncertain significance	not specified	2015-03-30	criteria provided, single submitter	clinical testing	The p.Pro29832Thr variant in TTN has not been previously reported in individuals with cardiomyopathy, but has been identified in 4/11470 of Latino chromosomes a nd 10/65646 European chromosomes by the Exome Aggregation Consortium (ExAC, http ://exac.broadinstitute.org; dbSNP rs373876117). Computational prediction tools a nd conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Pro29832Thr varia nt is uncertain.
GeneDx	RCV000766676	SCV000617199	uncertain significance	not provided	2018-06-01	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the TTN gene. The P30759T variant (reported as P29832T due to the use of alternate nomenclature) has been published two patients with sudden unexplained death (SUD), however, both of these patients harbored additional cardiogenetic variants (Campuzano et al., 2014; Sanchez et al., 2016). The P30759T variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P30759T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, this is a missense variant in a gene in which most reported pathogenic variants associated with cardiomyopathy are truncating/loss-of-function (Stenson et al., 2014).
Invitae	RCV000525107	SCV000643972	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-12-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001130879	SCV001290474	benign	Myopathy, myofibrillar, 9, with early respiratory failure	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV001130880	SCV001290475	uncertain significance	Early-onset myopathy with fatal cardiomyopathy	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001130881	SCV001290476	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001133849	SCV001293563	uncertain significance	Dilated cardiomyopathy 1G	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001133850	SCV001293564	benign	Tibial muscular dystrophy	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Mayo Clinic Laboratories, Mayo Clinic	RCV000766676	SCV001714028	uncertain significance	not provided	2021-04-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002365162	SCV002666773	uncertain significance	Cardiovascular phenotype	2019-05-11	criteria provided, single submitter	clinical testing	The p.P23335T variant (also known as c.70003C>A), located in coding exon 176 of the TTN gene, results from a C to A substitution at nucleotide position 70003. The proline at codon 23335 is replaced by threonine, an amino acid with highly similar properties. This variant (reported as p.P29832T, c.89494C>A) has been detected in individuals from a sudden death cohort, where it co-occurred with other variants in TTN (Sanchez O et al. PLoS ONE, 2016 Dec;11:e0167358). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000766676	SCV003825521	uncertain significance	not provided	2023-10-04	criteria provided, single submitter	clinical testing
Clinical Genetics, Academic Medical Center	RCV000766676	SCV001923112	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000766676	SCV001955430	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000766676	SCV001969087	uncertain significance	not provided		no assertion criteria provided	clinical testing