ClinVar Miner

Submissions for variant NM_000363.4(TNNI3):c.586G>A (p.Asp196Asn) (rs104894727)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CSER_CC_NCGL; University of Washington Medical Center RCV000148897 SCV000190643 likely pathogenic Primary familial hypertrophic cardiomyopathy 2014-06-01 no assertion criteria provided research
Color RCV000777480 SCV000913342 likely pathogenic Cardiomyopathy 2018-08-14 criteria provided, single submitter clinical testing Likely Pathogenic variant based on current evidence: This missense variant is located in the C-terminal mobile domain of the TNNI3 protein. Computational prediction tools and conservation analyses suggest that this variant may impact the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant. While this variant is rare in the general population (3/277204 chromosomes in the Genome Aggregation Database (gnomAD)), this variant has been reported in over 10 individuals affected with hypertrophic cardiomyopathy (PMID: 12707239, 15607392, 24111713, 25524337, 26914223, 27532257). In two unrelated families, this variant was found in 4 of 7 affected family members (PMID: 15607392). Based on available evidence, this variant is classified as Likely Pathogenic.
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 likely pathogenic Hypertrophic cardiomyopathy 2018-05-07 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 reported to segregate with hypertrophic cardiomyopathy (HCM) in a family (PMID: 15607392) and has been reported in several unrelated individuals affected with this disease (PMID: 11815426, 26914223, 12707239, 25524337, 24111713, 15607392, 27532257). ClinVar contains an entry for this variant (Variation ID: 12422). This variant lies into a functional protein domain (p.Leu174-p.Ser210) that stabilizes the Ca2+-activated state of tropomyosin on actin filaments (PMID: 20035081, 21777381). Most of the TNNI3 variants associated with HCM lie within this domain (PMID: 26440512). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary this is a rare variant that has been reported in several affected individuals and families and it affects a region that is known to be important for protein function. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000148897 SCV000059960 likely pathogenic Primary familial hypertrophic cardiomyopathy 2017-08-30 criteria provided, single submitter clinical testing The p.Asp196Asn variant in TNNI3 has been reported in 7 individuals with HCM and segregated with disease in 3 affected relatives from 2 families (Niimura 2002, Richard 2003, Mogensen 2004, Murphy 2016, LMM data). This variant has been identified in 3/126706 of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs104894727). Computational prediction tools and conservation analysis suggest that the p.Asp196Asn variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, the p.Asp196Asn variant is likely pathogenic.
OMIM RCV000013234 SCV000033481 pathogenic Familial hypertrophic cardiomyopathy 7 2002-01-29 no assertion criteria provided literature only

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