Submissions for variant NM_000363.5(TNNI3):c.407G>A (p.Arg136Gln)

dbSNP: rs730881069

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159213	SCV000209159	likely pathogenic	not provided	2024-07-12	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23140321, 27532257, 20624503, 22765922, 24510615, 34426522, 33336002, 33193569, 33087929, 37652022, 25132132, 38880420, 30297972, 35176171, 24793961, 20800588)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000167999	SCV000218650	pathogenic	Hypertrophic cardiomyopathy	2023-09-21	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. ClinVar contains an entry for this variant (Variation ID: 181576). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 20624503, 22765922, 24510615, 27532257, 28356264; Invitae). This variant is present in population databases (rs730881069, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 136 of the TNNI3 protein (p.Arg136Gln).
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769526	SCV000900921	likely pathogenic	Cardiomyopathy	2022-11-30	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000159213	SCV000928159	likely pathogenic	not provided	2019-01-08	criteria provided, single submitter	clinical testing
New York Genome Center	RCV001781500	SCV002025676	likely pathogenic	Hypertrophic cardiomyopathy 7	2020-04-24	criteria provided, single submitter	clinical testing	The c.407G>A, p.Arg136Gln variant has 0.0004% allele frequency in the gnomAD database (1 out of 248,592 heterozygous alleles), indicating this is a rare allele. This sequence change has been observed in individuals affected with hypertrophic cardiomyopathy [PMID: 28356264; PMID:27532257; PMID: 24510615; PMID: 22765922; PMID: 20624503]. In silico tools(SIFT, PolyPhen-2, Align-GVGD, REVEL, and CADD) suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Based on available evidence this variant has been classified as Likely Pathogenic.
Ambry Genetics	RCV002321670	SCV002626501	likely pathogenic	Cardiovascular phenotype	2024-05-10	criteria provided, single submitter	clinical testing	The p.R136Q variant (also known as c.407G>A), located in coding exon 7 of the TNNI3 gene, results from a G to A substitution at nucleotide position 407. The arginine at codon 136 is replaced by glutamine, an amino acid with highly similar properties. This variant has been reported in multiple individuals with hypertrophic cardiomyopathy (Millat G et al. Eur J Med Genet. 2010 Jul;53(5):261-7; Coto E et al. J Mol Diagn, 2012 Sep;14:518-24; T; Kapplinger JD et al. J Cardiovasc Transl Res, 2014 Apr;7:347-61; Walsh R et al. Genet. Med., 2017 Feb;19:192-203; Osadnik T et al. Kardiol Pol. 2022 Feb;80(4):482-484). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic for autosomal dominant TNNI3-related cardiomyopathy; however, its clinical significance for autosomal recessive TNNI3-related dilated cardiomyopathy is uncertain.
All of Us Research Program, National Institutes of Health	RCV000167999	SCV004838446	uncertain significance	Hypertrophic cardiomyopathy	2023-12-14	criteria provided, single submitter	clinical testing	This variant has been reported in multiple individuals with hypertrophic cardiomyopathy (PMID: 20624503, 20800588, 24510615, 24793961, 25132132, 27532257, 30297972, 35176171). This variant is located in a well-established functional domain of the protein where other pathogenic or likely pathogenic variants have been described (PMID: 20624503). This variant is present in 1/248592 total alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/).