Submissions for variant NM_000363.5(TNNI3):c.5C>T (p.Ala2Val)

dbSNP: rs397516359

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036309	SCV000059961	uncertain significance	not specified	2019-06-28	criteria provided, single submitter	clinical testing	The p.Ala2Val variant in TNNI3 has been reported as homozygous in 2 individuals with DCM and segregated in the homozygous state in 1 affected sibling (Murphy 2004, LMM data). In vitro functional studies provide some evidence that the p.Ala2Val variant may impact protein function (Murphy 2004, Henze 2013). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. This variant has been identified in 0.03% (8/30592) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency raises the possibility that the variant does not cause disease in the heterozygous state but is not inconsistent with a recessive mode of inheritance. In summary, due to conflicting evidence, the clinical significance of the p.Ala2Val variant is uncertain. ACMG/AMP Criteria applied: PP1, PM3_Supporting, PS3_Supporing, BS1_Supporting, BP4.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769534	SCV000900929	uncertain significance	Cardiomyopathy	2019-12-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000769534	SCV001360401	uncertain significance	Cardiomyopathy	2023-06-08	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 2 of the TNNI3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant disrupts the interaction between troponin I and troponin T (PMID: 15070570), and affects myofilament function (PMID: 22940544). This variant has been reported in homozygous state in two siblings affected with dilated cardiomyopathy (PMID: 15070570); their parents and another sibling were all healthy heterozygous carriers. This variant has also been reported in homozygous state in an individual affected with childhood-onset dilated cardiomyopathy (PMID: 32870709) and in unspecified zygosity in another individual affected with childhood-onset dilated cardiomyopathy (PMID: 32746448). This variant has also been identified in 8/248866 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.
GeneDx	RCV001753445	SCV001985384	uncertain significance	not provided	2019-11-19	criteria provided, single submitter	clinical testing	Reported as a homozygous variant in two siblings with DCM; both heterozygous parents and one heterozygous sibling were reported to have a normal cardiac work-up (Murphy et al., 2004); Functional studies have demonstrated conflicting results regarding the impact on ATPase regulation and troponin function (Murphy et al., 2004; Carballo et al., 2009; Henze et al., 2013); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 43397; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 19590045, 31568572, 22940544, 15070570, 31534214, 32870709)
AiLife Diagnostics, AiLife Diagnostics	RCV001753445	SCV002501800	uncertain significance	not provided	2021-07-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002513379	SCV003282082	likely pathogenic	Hypertrophic cardiomyopathy	2024-07-19	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2 of the TNNI3 protein (p.Ala2Val). This variant is present in population databases (rs397516359, gnomAD 0.03%). This missense change has been observed in individuals with autosomal recessive dilated cardiomyopathy (PMID: 32870709; Invitae). ClinVar contains an entry for this variant (Variation ID: 43397). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects TNNI3 function (PMID: 15070570, 22940544). 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.
All of Us Research Program, National Institutes of Health	RCV002513379	SCV004821905	uncertain significance	Hypertrophic cardiomyopathy	2024-07-10	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 2 of the TNNI3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant disrupts the interaction between troponin I and troponin T (PMID: 15070570), and affects myofilament function (PMID: 22940544). This variant has been reported in homozygous state in two siblings affected with dilated cardiomyopathy (PMID: 15070570); their parents and another sibling were all healthy heterozygous carriers. This variant has also been reported in homozygous state in an individual affected with childhood-onset dilated cardiomyopathy (PMID: 32870709) and in unspecified zygosity in another individual affected with childhood-onset dilated cardiomyopathy (PMID: 32746448). This variant has also been identified in 8/248866 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV004760353	SCV005374418	uncertain significance	Hypertrophic cardiomyopathy 7	2024-09-22	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000013240	SCV005399507	likely pathogenic	Dilated cardiomyopathy 2A	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as likely pathogenic. Following criteria are met: 0103 - Gain of function and loss of function are reported mechanisms of disease in this gene. The former is associated with familial restrictive cardiomyopathy 1 (MIM#115210) and hypertrophic cardiomyopathy 7 (MIM#613690), while the latter is associated with dilated cardiomyopathy 1FF (MIM#613286) (PMID: 19914256, 21533915). (I) 0108 - This gene is associated with both recessive and dominant disease. Although predominantly associated with autosomal dominant disease, there are emerging reports of autosomal recessive cardiomyopathy (PMID: 15070570, 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) 0200 - Variant is predicted to result in a missense amino acid change from alanine to valine. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.001 (8 heterozygotes, 0 homozygotes). (SP) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0600 - Variant is located in the annotated Troponin I N-extension domain (Pfam). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. This variant has been described in a DCM family with two homozygous affected siblings, where the heterozygous third sibling and parents were unaffected (PMID: 15070570). This variant was also reported in a young woman with DCM, although the zygosity was not stated (PMID: 31534214). ClinVar has 4 VUS entries for this variant by clinical testing; at least one of these was identified in the homozygous state in an individual with DCM (personal correspondence). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. In vitro studies indicate that this variant results in reduced binding to cTnT and altered myofilament activation, although the relevance of this evidence to disease pathology is unknown (PMID: 15070570, 22940544). (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (LABID). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Ambry Genetics	RCV004991983	SCV005519948	uncertain significance	Cardiovascular phenotype	2024-12-04	criteria provided, single submitter	clinical testing	The p.A2V variant (also known as c.5C>T), located in coding exon 1 of the TNNI3 gene, results from a C to T substitution at nucleotide position 5. The alanine at codon 2 is replaced by valine, an amino acid with similar properties. This variant has been identified in the homozygous state and/or in conjunction with other TNNI3 variant(s) in individual(s) with features consistent withTNNI3-related dilated cardiomyopathy; however, heterozygotes have been reported as unaffected (Murphy RT et al. Lancet, 2004 Jan;363:371-2; Al-Hassnan ZN et al. Circ Genom Precis Med, 2020 Oct;13:504-514; Bagnall RD et al. Circ Genom Precis Med, 2022 Dec;15:e003686). Functional studies suggest this variant may impact protein function; however, additional evidence is needed to confirm these findings (Murphy RT et al. Lancet, 2004 Jan;363:371-2; Carballo S et al. Circ Res, 2009 Aug;105:375-82; Henze M et al. Biochim Biophys Acta. 2013 Apr;1833(4):823-32). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for an autosomal dominant disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). Based on the available evidence, the clinical significance of this variant remains unclear.
OMIM	RCV000013240	SCV000033487	pathogenic	Dilated cardiomyopathy 2A	2009-08-14	no assertion criteria provided	literature only