Submissions for variant NM_001276345.2(TNNT2):c.321G>T (p.Lys107Asn)

dbSNP: rs397516459

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000788201	SCV000060233	uncertain significance	not provided	2022-08-09	criteria provided, single submitter	clinical testing	The p.Lys97Asn variant in TNNT2 has been previously reported in at least 4 individuals with hypertrophic cardiomyopathy (HCM) and segregated with disease in at least 4 affected relatives from two families, 3 of whom were tested in a research laboratory (Harada 2004 PMID: 15631686, Coppini 2014 PMID: 25524337, Walsh 2017 PMID: 27532257, LMM data). This variant was also identified in 1 individual with DCM and a family history of HCM (possible end-stage HCM, LMM data). This variant has also been reported in ClinVar (Variation ID 43631) and has been identified in 0.0009% (1/113760) European chromosomes in gnomAD (https://gnomad.broadinstitute.org/). In vitro functional studies provide conflicting evidence on whether this variant impacts protein function (Gangadharan 2017 PMID: 28973951, Pettinato 2020 PMID: 33025817). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS4_Supporting, PP1, PM2_Supporting, PP3.
Blueprint Genetics	RCV000788201	SCV000927237	pathogenic	not provided	2017-04-22	criteria provided, single submitter	clinical testing
Invitae	RCV000791922	SCV000931191	pathogenic	Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3	2023-10-18	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 97 of the TNNT2 protein (p.Lys97Asn). This variant is present in population databases (rs397516459, gnomAD 0.0009%). This missense change has been observed in individuals with TNNT2-related conditions (PMID: 21185001, 25524337, 27532257; Invitae). ClinVar contains an entry for this variant (Variation ID: 43631). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TNNT2 protein function. Experimental studies have shown that this missense change affects TNNT2 function (PMID: 33025817). For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV003450691	SCV004181475	likely pathogenic	Dilated cardiomyopathy 1D	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003450692	SCV004181476	likely pathogenic	Cardiomyopathy, familial restrictive, 3	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003450690	SCV004181477	likely pathogenic	Hypertrophic cardiomyopathy 2	2023-04-11	criteria provided, single submitter	clinical testing
Human Genetics Bochum, Ruhr University Bochum	RCV003886369	SCV004704565	likely pathogenic	See cases	2023-11-13	criteria provided, single submitter	clinical testing	ACMG criteria used to clasify this variant: PS3_MOD, PS4_MOD, PP3_MOD, PM2_SUP
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