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

dbSNP: rs397516359

Total submissions: 7

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
Invitae	RCV002513379	SCV003282082	likely pathogenic	Hypertrophic cardiomyopathy	2024-01-22	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.
OMIM	RCV000013240	SCV000033487	pathogenic	Dilated cardiomyopathy 2A	2009-08-14	no assertion criteria provided	literature only