Submissions for variant NM_000363.5(TNNI3):c.544G>A (p.Glu182Lys)

dbSNP: rs397516355

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036303	SCV000059955	pathogenic	Primary dilated cardiomyopathy	2014-09-10	criteria provided, single submitter	clinical testing	The Glu182Lys variant in TNNI3 has been identified by our laboratory as de novo in 1 African American neonate with DCM and 1 Caucasian infant with DCM. In addit ion, it has not been identified in large population studies. Computational predi ction tools and conservation analysis do not provide strong support for or again st an impact to the protein. In summary, this variant meets our criteria to be c lassified as pathogenic (http://www.partners.org/personalizedmedicine/LMM) based upon de novo occurrence in multiple cases.
GeneDx	RCV000159235	SCV000209181	pathogenic	not provided	2012-10-25	criteria provided, single submitter	clinical testing	The Glu182Lys mutation in the TNNI3 gene has been reported in association with cardiomyopathy (Lakdawala N et al., 2012). Lakdawla et al. reported Glu182Lys occurred de novo in one patient with DCM and it was absent from approximately 400 control samples. Also, the NHLBI ESP Exome Variant Server reports Glu182Lys was not observed in approximately 6,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Glu182Lys results in a non-conservative amino acid substitution of a negatively charged Glutamic acid with a positively charged Lysine at a position that is highly conserved across species. Furthermore, mutations in nearby codons (Lys183Asn, Lys183Glu, Asn185Lys, Arg186Gln) have been reported in association with cardiomyopathy, supporting the functional importance of this region of the protein. In summary, Glu182Lys in the TNNI3 gene is interpreted as a disease-causing mutation. The variant is found in DCM panel(s).
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170613	SCV001333202	likely pathogenic	Cardiomyopathy	2018-12-12	criteria provided, single submitter	clinical testing
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV002468559	SCV002764935	pathogenic	Dilated cardiomyopathy 1FF	2021-08-02	criteria provided, single submitter	clinical testing
Invitae	RCV002513378	SCV003443937	pathogenic	Hypertrophic cardiomyopathy	2022-01-05	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. 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: "Benign"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 43392). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 22464770, 24503780, 27532257, 32458740). In at least one individual the variant was observed to be de novo. This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 182 of the TNNI3 protein (p.Glu182Lys).
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000036303	SCV000804930	likely pathogenic	Primary dilated cardiomyopathy	2015-10-12	no assertion criteria provided	clinical testing