Submissions for variant NM_001276345.2(TNNT2):c.451del (p.Arg151fs)

dbSNP: rs730881115

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159327	SCV000209273	uncertain significance	not provided	2018-10-30	criteria provided, single submitter	clinical testing	The c.421delC variant of uncertain significance in the TNNT2 gene has reported in multiple individuals with DCM (Millat et al., 2011; Hirtle-Lewis et al., 2013; Broch et al., 2015; Meng et al., 2017) and also has been reported in one individual with HCM (van Velzen et al., 2016). Millat et al. (2011) identified this variant in an individual with DCM and observed segregation with disease in three affected family members. The c.421delC variant is observed in 14/126,390 (0.01%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). This variant causes a shift in reading frame starting at codon arginine 141, changing it to a glycine, and creating a premature stop codon at position 41 of the new reading frame, denoted p.Arg141GlyfsX41. This variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. However, the vast majority of variants in TNNT2 are missense changes, indicating haploinsufficiency of TNNT2 may not be sufficient to cause cardiomyopathy. Some truncating variants have been reported in association with familial cardiomyopathy (Stenson et al., 2014), however these changes are commonly present at the last and penultimate exons of the TNNT2 gene.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Center for Medical Genetics Ghent, University of Ghent	RCV000240641	SCV000299244	uncertain significance	Dilated cardiomyopathy 1D	2016-05-25	criteria provided, single submitter	clinical testing	This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. To date, it is not known whether loss-of-function is a disease mechanism for the TNNT2 gene.
Ambry Genetics	RCV000619254	SCV000736849	uncertain significance	Cardiovascular phenotype	2023-07-10	criteria provided, single submitter	clinical testing	The c.421delC variant, located in coding exon 9 of the TNNT2 gene, results from a deletion of one nucleotide at nucleotide position 421, causing a translational frameshift with a predicted alternate stop codon (p.R141Gfs*41). This alteration has been reported in a case of familial dilated cardiomyopathy and was reported to segregate with disease in the family (Millat G et al. Eur J Med Genet 2011 Aug;54:e570-5). This alteration has also been reported in an infant with dilated cardiomyopathy, congenital heart disease and respiratory distress and has been seen in a hypertrophic cardiomyopathy (HCM) cohort (Meng L et al. JAMA Pediatr, 2017 12;171:e173438; van Velzen HG et al. Circ Genom Precis Med, 2018 04;11:e001896). This alteration has also been seen in an exome cohort, but cardiovascular history was not provided (Retterer K et al. Genet. Med., 2016 Jul;18:696-704). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. However, loss of function of TNNT2 has not been clearly established as a mechanism of disease. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000698376	SCV000827036	uncertain significance	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg141Glyfs*41) in the TNNT2 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in TNNT2 cause disease. This variant is present in population databases (rs730881115, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with dilated cardiomyopathy (PMID: 21846512, 26468400, 28973083). ClinVar contains an entry for this variant (Variation ID: 181635). 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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000845506	SCV000987608	likely pathogenic	Primary familial hypertrophic cardiomyopathy	2023-09-26	criteria provided, single submitter	clinical testing	PVS1_Mod;PS4_Supp;PM2;PP1
CeGaT Center for Human Genetics Tuebingen	RCV000159327	SCV001150580	uncertain significance	not provided	2023-11-01	criteria provided, single submitter	clinical testing	TNNT2: PS4:Moderate, PP1
Color Diagnostics, LLC DBA Color Health	RCV001187860	SCV001354760	uncertain significance	Cardiomyopathy	2023-01-18	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 10 of the TNNT2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 21846512, 26468400), including four affected individuals from a family (PMID: 21846512). This variant has also been identified in 14/281472 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Clinical relevance of loss-of-function truncation and splice variants in the TNNT2 gene is not clearly established. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000240641	SCV001367502	uncertain significance	Dilated cardiomyopathy 1D	2019-10-25	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PP5.
AiLife Diagnostics, AiLife Diagnostics	RCV000159327	SCV002501382	uncertain significance	not provided	2021-10-09	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000159327	SCV004224773	uncertain significance	not provided	2023-06-16	criteria provided, single submitter	clinical testing	PP1