Submissions for variant NM_000363.5(TNNI3):c.586G>A (p.Asp196Asn)

gnomAD frequency: 0.00001  dbSNP: rs104894727

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000461416	SCV000059960	likely pathogenic	Hypertrophic cardiomyopathy	2021-02-21	criteria provided, single submitter	clinical testing	The p.Asp196Asn variant in TNNI3 has been reported in at least 12 individuals with HCM and segregated with disease in 3 affected individuals from 2 families (Niimura 2002 PMID:11815426, Richard 2003 PMID:12707239, Mogensen 2004 PMID:15607392, Coppini 2014 PMID: 25524337, Berge 2014 PMID:24111713, Murphy 2016 PMID:26914223, Walsh 2017 PMID:27532257, Norrish 2019 PMID:31006259, LMM data). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 12422) and has been identified in 0.002% (2/128706) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses are consistent with pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HCM. ACMG/AMP criteria applied: PS4_Strong, PP1, PM2_Supporting, PP3.
GeneDx	RCV000159246	SCV000209192	likely pathogenic	not provided	2021-02-10	criteria provided, single submitter	clinical testing	Mogensen et al. (2004) reported the D196N variant to be present in four affected individuals from two families with HCM; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20035081, 26526134, 23299917, 25637381, 11815426, 12707239, 25524337, 24111713, 15607392, 26914223, 27532257, 28971120, 21777381, 26440512, 26199943, 31006259)
Invitae	RCV000461416	SCV000551895	pathogenic	Hypertrophic cardiomyopathy	2023-09-08	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 12422). For these reasons, this variant has been classified as Pathogenic. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 11815426, 12707239, 15607392, 24111713, 25524337, 26914223, 27532257). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs104894727, gnomAD 0.002%). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 196 of the TNNI3 protein (p.Asp196Asn).
Color Diagnostics, LLC DBA Color Health	RCV000777480	SCV000913342	likely pathogenic	Cardiomyopathy	2023-05-11	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 196 in the C-terminal mobile domain of the TNNI3 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over 10 individuals affected with hypertrophic cardiomyopathy (PMID: 12707239, 15607392, 24111713, 25524337, 26914223, 27532257), and in an individual with a family history of hypertrophic cardiomyopathy (PMID: 34363016). In two unrelated families, this variant was identified in 4 of 7 family members affected with hypertrophic cardiomyopathy (PMID: 15607392). This variant has been identified in 2/280974 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000013234	SCV001754791	likely pathogenic	Hypertrophic cardiomyopathy 7	2019-09-26	criteria provided, single submitter	clinical testing	The c.586G>A (p.Asp196Asn) variant in the TNNI3 gene has been reported in multiple individuals affected with hypertrophic cardiomyopathy (PMID 11815426, 12707239, 15607392, 24111713, 25524337). This variant is observed at an ultra-low frequency in the general population (gnomAD database 2/280974) and is reported to be damaging by multiple bioinformatics algorithms. For these reasons, this variant has been classified as Likely Pathogenic.
Laan Lab, Human Genetics Research Group, University of Tartu	RCV000013234	SCV002538622	likely pathogenic	Hypertrophic cardiomyopathy 7	2021-05-01	criteria provided, single submitter	research
CeGaT Center for Human Genetics Tuebingen	RCV000159246	SCV002563546	likely pathogenic	not provided	2022-07-01	criteria provided, single submitter	clinical testing	TNNI3: PM1, PM5, PP1, PS4:Supporting
Ambry Genetics	RCV002354157	SCV002652676	likely pathogenic	Cardiovascular phenotype	2022-12-29	criteria provided, single submitter	clinical testing	The p.D196N variant (also known as c.586G>A), located in coding exon 8 of the TNNI3 gene, results from a G to A substitution at nucleotide position 586. The aspartic acid at codon 196 is replaced by asparagine, an amino acid with highly similar properties. This variant was identified in multiple individuals with hypertrophic cardiomyopathy (HCM) (Niimura H et al. Circulation, 2002 Jan;105:446-51; Richard P et al. Circulation, 2003 May;107:2227-32; Mogensen J et al. J. Am. Coll. Cardiol., 2004 Dec;44:2315-25; Berge KE et al. Clin. Genet., 2014 Oct;86:355-60; Coppini R et al. J. Am. Coll. Cardiol., 2014 Dec;64:2589-2600; Murphy SL et al. J Cardiovasc Transl Res, 2016 Apr;9:153-61; Walsh R et al. Genet. Med., 2017 02;19:192-203). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002496340	SCV002811559	likely pathogenic	Dilated cardiomyopathy 2A; Cardiomyopathy, familial restrictive, 1; Dilated cardiomyopathy 1FF; Hypertrophic cardiomyopathy 7	2022-04-21	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000777480	SCV004239772	likely pathogenic	Cardiomyopathy	2022-09-01	criteria provided, single submitter	clinical testing
OMIM	RCV000013234	SCV000033481	pathogenic	Hypertrophic cardiomyopathy 7	2002-01-29	no assertion criteria provided	literature only
CSER _CC_NCGL, University of Washington	RCV000148897	SCV000190643	likely pathogenic	Primary familial hypertrophic cardiomyopathy	2014-06-01	no assertion criteria provided	research