ClinVar Miner

Submissions for variant NM_000363.5(TNNI3):c.586G>A (p.Asp196Asn) (rs104894727)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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 2018-05-22 criteria provided, single submitter clinical testing The D196N likely pathogenic variant in the TNNI3 gene has been published multiple times in association with HCM (Niimura et al., 2002; Richard et al., 2003; Mogensen et al., 2004; Coppini et al., 2014; Berge et al., 2014; Murphy et al., 2016; Walsh et al., 2017). Mogensen et al. (2004) reported the D196N variant to be present in four affected individuals from two families with HCM. This variant has also been classified as a likely pathogenic variant by other clinical laboratories in ClinVar (SCV000059960.5, SCV000551895.2; Landrum et al., 2016).The D196N variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The D196N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Finally, pathogenic and likely pathogenic missense variants in nearby residues (R192C, p.R192P, R192H, N194K, L198V, S199N) have been reported previously at GeneDx and have been reported in the Human Gene Database in association with HCM (Stenson et al., 2014). However, functional studies have not been performed to further support the pathogenicity of this variant.Therefore, D196N in the TNNI3 gene is interpreted as a likely pathogenic variant.
Invitae RCV000461416 SCV000551895 pathogenic Hypertrophic cardiomyopathy 2020-10-06 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 196 of the TNNI3 protein (p.Asp196Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs104894727, ExAC 0.001%). This variant has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 11815426, 26914223, 12707239, 25524337, 24111713, 15607392, 27532257). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12422). 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). For these reasons, this variant has been classified as Pathogenic.
Color Health, Inc RCV000777480 SCV000913342 likely pathogenic Cardiomyopathy 2019-09-19 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000013234 SCV001754791 likely pathogenic Familial 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.
OMIM RCV000013234 SCV000033481 pathogenic Familial 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

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