ClinVar Miner

Submissions for variant NM_000364.4(TNNT2):c.321G>T (p.Lys107Asn) (rs397516459)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000036578 SCV000060233 likely pathogenic Hypertrophic cardiomyopathy 2015-03-11 criteria provided, single submitter clinical testing The p.Lys97Asn variant in TNNT2 has been previously reported in 1 individual wit h HCM (Cardiogenomics) and in 1 unaffected individual with a family history of H CM and sudden cardiac death (Maron 2011). In addition, this variant has been ide ntified by our laboratory in 1 adult with DCM and a family history of HCM (possi ble end-stage HCM) and in 1 adult with HCM and was found to segregate with disea se in at least 4 affected relatives from two families, 3 of whom were tested in a research laboratory (LMM unpublished data). This variant was absent from large population studies. Lysine (Lys) at position 97 is highly conserved in evolutio n and the change to asparagine (Asn) was predicted to be pathogenic using a comp utational tool clinically validated by our laboratory. This tool's pathogenic pr ediction is estimated to be correct 94% of the time (Jordan 2011). In summary, a lthough additional studies are required to fully establish its clinical signific ance, the p.Lys97Asn variant is likely pathogenic.
Blueprint Genetics RCV000788201 SCV000927237 pathogenic not provided 2017-04-22 criteria provided, single submitter clinical testing
Invitae RCV000791922 SCV000931191 uncertain significance Familial hypertrophic cardiomyopathy 2; Left ventricular noncompaction 6; Familial restrictive cardiomyopathy 3 2019-01-03 criteria provided, single submitter clinical testing This sequence change replaces lysine with asparagine at codon 97 of the TNNT2 protein (p.Lys97Asn). 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 (ExAC no frequency). This variant has been observed in individuals affected with hypertrophic cardiomyopathy (PMID: 25524337, 27532257) and in a healthy individual with family history of hypertrophic cardiomyopathy and sudden death (PMID: 21185001). ClinVar contains an entry for this variant (Variation ID: 43631). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000223847 SCV000280520 uncertain significance not specified 2011-12-19 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease

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