ClinVar Miner

Submissions for variant NM_000363.5(TNNI3):c.579G>C (p.Lys193Asn) (rs397516358)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000036307 SCV000059959 uncertain significance not specified 2012-04-06 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The Lys193Asn v ariant in TNNI3 has not been reported in the literature, but has been identified in 1 individual with HCM (this individual's son) out of >2,100 Caucasian proban ds tested by our laboratory. This low frequency is consistent with a pathogenic role. Computational analyses (biochemical amino acid properties, conservation, A lignGVGD, PolyPhen2, and SIFT) suggest that the Lys193Asn variant may impact the protein, though this information is not predictive enough to determine pathogen icity. Additional information is needed to fully assess the clinical significan ce of the Lys193Asn variant.
Invitae RCV000234031 SCV000284660 uncertain significance Hypertrophic cardiomyopathy 2015-11-12 criteria provided, single submitter clinical testing This sequence change replaces lysine with asparagine at codon 193 of the TNNI3 protein (p.Lys193Asn). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and asparagine. This variant is not present in population databases (rs397516358, ExAC no frequency). ClinVar contains an entry for this variant (Variation ID: 43396). This variant was observed in this patient's sibling who was diagnosed with hypertrophic cardiomyopathy, and was found to be absent in this patient's father. This patient's mother, who was affected with hypertrophic cardiomyopathy and had a family history consistent with inherited cardiovascular disease, was not genotyped. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. This missense change is located in a region of the TNNI3 protein where a significant number of previously reported TNNI3 missense mutations are found (PMID: 15607392). These observations suggest that a previously unreported missense substitution within this region may affect protein function, but experiments have not been done to test this possibility. In summary, the observation in this family is suggestive of segregation with hypertrophic cardiomyopathy and this variant found in a region of the protein known to be important for protein function. However, the segregation evidence is limited and functional impact has not been confirmed at this time. For these reasons, this change has been classified as a Variant of Uncertain Significance.

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