ClinVar Genomic variation as it relates to human health

This sequence change creates a premature translational stop signal (p.Arg98*) in the TNNI3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TNNI3 are known to be pathogenic (PMID: 31568572, 34036930, 35838873). This variant is present in population databases (rs730881068, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with autosomal recessive dilated cardiomyopathy (PMID: 36252119, 36981019). ClinVar contains an entry for this variant (Variation ID: 181575). For these reasons, this variant has been classified as Pathogenic.

Reported in association with cardiomyopathy, however, additional clinical information was not provided (Walsh et al., 2017; Lu et al., 2018); Reported in a participant in the Framingham heart study (FHS) who had a normal left ventricular wall thickness and a physiological risk factor for heart disease (Bick et al., 2012); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is not a known mechanism of disease; This variant is associated with the following publications: (PMID: 22958901, 27532257, 28436080, 30165862)

This variant changes 1 nucleotide in exon 6 of the TNNI3 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. An experimental functional study has shown that this variant may cause reduced protein expression and increased Ca2+-sensitivity (PMID: 28436080). However, clinical relevance of this observation is not clear. This variant has been reported in individuals affected with dilated cardiomyopathy (PMID 28436080, 30165862, 34286374), in an individual affected with hypertrophic cardiomyopathy (PMID: 27532257), and in a fetus affected with stillbirth (PMID: 30615648). This variant has also been reported in homozygosity in an infant affected with early-onset dilated cardiomyopathy (PMID: 36981019); both heterozygous parents were apparently unaffected but did not receive cardiological evaluations. This variant has been identified in 16/280804 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Clinical relevance of loss-of-function TNNI3 truncation variants in autosomal dominant cardiovascular disorders 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.

This variant changes 1 nucleotide in exon 6 of the TNNI3 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. An experimental functional study has shown that this variant may cause reduced protein expression and increased Ca2+-sensitivity (PMID: 28436080). However, clinical relevance of this observation is not clear. This variant has been reported in individuals affected with dilated cardiomyopathy (PMID 28436080, 30165862, 34286374), in an individual affected with hypertrophic cardiomyopathy (PMID: 27532257), and in a fetus affected with stillbirth (PMID: 30615648). This variant has also been reported in homozygosity in an infant affected with early-onset dilated cardiomyopathy (PMID: 36981019); both heterozygous parents were apparently unaffected but did not receive cardiological evaluations. This variant has been identified in 16/280804 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Clinical relevance of loss-of-function TNNI3 truncation variants in autosomal dominant cardiovascular disorders 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.

The p.R98* variant (also known as c.292C>T), located in coding exon 6 of the TNNI3 gene, results from a C to T substitution at nucleotide position 292. This changes the amino acid from an arginine to a stop codon within coding exon 6. This variant has been reported in individual(s) from dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) cohorts, but clinical details were limited (Bollen IAE et al. J Physiol, 2017 Jul;595:4677-4693; Walsh R et al. Genet Med, 2017 Feb;19:192-203; Lu C et al. J Transl Med, 2018 Aug;16:241; Gran F et al. Eur J Pediatr, 2022 Jan;181:287-294). This variant has been identified in the homozygous state in individual(s) with features consistent with pediatric-onset dilated cardiomyopathy whose heterozygous relatives were reportedly unaffected (Bagnall RD. Circ Genom Precis Med. 2022 Dec;15(6):e003686; Sorrentino U. Genes (Basel). 2023 Mar;14(3)). Functional studies from one group suggest this variant may alter calcium sensitivity; however, the physiological relevance of this finding is unclear (Bollen IAE et al. J Physiol, 2017 Jul;595:4677-4693). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Although biallelic loss of function of TNNI3 has been associated with autosomal recessive dilated cardiomyopathy, haploinsufficiency of TNNI3 has not been established as a mechanism of disease for autosomal dominant cardiomyopathy. Based on the supporting evidence, this variant is expected to be causative of autosomal recessive dilated cardiomyopathy when present along with a second pathogenic variant on the other allele; however, its clinical significance for autosomal dominant cardiomyopathy is unclear.

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0103 - Gain of function and loss of function are reported mechanisms of disease in this gene. Gain of function is associated with familial restrictive cardiomyopathy 1 (MIM#115210) and hypertrophic cardiomyopathy 7 (HCM; MIM#613690), while the latter is associated with dilated cardiomyopathy 1FF (DCM; MIM#613286) (PMIDs: 19914256, 21533915). (I) 0108 - This gene is associated with both recessive and dominant disease. The recessive form of inheritance is the exception and has only been reported in a few families (PMIDs: 15070570, 23270746, 31568572). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 15607392). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 23270746). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0252 - This variant is homozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (16 heterozygotes, 0 homozygotes). (SP) 0708 - Other NMD variants comparable to the one identified in this case have conflicting previous evidence for pathogenicity. Most NMD variants reported in patients with cardiomyopathies are either VUS or conflicting, however p.(Asp113Alafs*2) has been regarded pathogenic for HCM (PMID: 27532257) and p.(Arg69Alafs*8) has been reported in a family with recessive DCM (PMID: 31568572). (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported as VUS, likely pathogenic and pathogenic (ClinVar, LOVD) in individuals with HCM (PMID: 27532257) or DCM (PMID: 28436080, 30065175, 30165862). It has also been detected in a case of stillbirth in a study screening heart disease genes (PMID: 30615648). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Heart biopsy of a patient with DCM showed increased calcium sensitivity and decreased length-dependent activation. In addition, this variant was shown to reduce expression of the troponin complex proteins and altered stoichiometry between the subunits. Exchange with wild-type troponin complex corrected troponin protein levels to 83% of controls (PMID: 28436080). (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (by segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

PM3