Submissions for variant NM_000363.5(TNNI3):c.150G>A (p.Lys50=)

dbSNP: rs730881086

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159257	SCV000209203	uncertain significance	not provided	2024-09-18	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 28359509, 35838873)
Color Diagnostics, LLC DBA Color Health	RCV001186290	SCV001352671	uncertain significance	Cardiomyopathy	2024-02-01	criteria provided, single submitter	clinical testing	This synonymous variant does not change the encoded amino acid at codon 50 of the TNNI3 protein, but it causes a G to A substitution at the last nucleotide of exon 4 of the TNNI3 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. An in-vitro exon trapping functional study has shown that this variant may cause exon skipping while preserving the reading-frame (PMID: 28359509). This variant has been reported in homozygous state in one individual affected with dilated cardiomyopathy and acute myocarditis (PMID: 28359509). This variant has been identified in 2/173946 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Clinical relevance of loss-of-function truncation and splice variants in the TNNI3 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001342061	SCV001535963	pathogenic	Hypertrophic cardiomyopathy	2025-01-22	criteria provided, single submitter	clinical testing	This sequence change affects codon 50 of the TNNI3 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the TNNI3 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with clinical features of autosomal recessive dilated cardiomyopathy (PMID: 28359509, 35838873; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 181598). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 4, but is expected to preserve the integrity of the reading-frame (PMID: 28359509, 35838873). For these reasons, this variant has been classified as Pathogenic.
All of Us Research Program, National Institutes of Health	RCV001342061	SCV004821887	uncertain significance	Hypertrophic cardiomyopathy	2023-11-28	criteria provided, single submitter	clinical testing	This synonymous variant does not change the encoded amino acid at codon 50 of the TNNI3 protein, but it causes a G to A substitution at the last nucleotide of exon 4 of the TNNI3 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. An in-vitro exon trapping functional study has shown that this variant may cause exon skipping while preserving the reading-frame (PMID: 28359509). This variant has been reported in homozygous state in one individual affected with dilated cardiomyopathy and acute myocarditis (PMID: 28359509). This variant has been identified in 2/173946 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Clinical relevance of loss-of-function truncation and splice variants in the TNNI3 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.
Ambry Genetics	RCV004019927	SCV004968956	uncertain significance	Cardiovascular phenotype	2022-03-16	criteria provided, single submitter	clinical testing	The c.150G>A (p.K50K) alteration is located in exon 4 (coding exon 4) of the TNNI3 gene. This alteration consists of a G to A substitution at nucleotide position 150. This nucleotide substitution does not change the amino acid at codon 50. However, this change occurs in the last nucleotide of Exon 4 (c.109_150) which makes it likely to have some effect on normal mRNA splicing. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.