Submissions for variant NM_000257.4(MYH7):c.4250C>T (p.Thr1417Ile)

dbSNP: rs1057524383

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000436927	SCV000535400	uncertain significance	not provided	2023-04-13	criteria provided, single submitter	clinical testing	Identified in a patient with HCM in published literature (Lopes et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); 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: 25351510, 34542152)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170994	SCV001333661	uncertain significance	Cardiomyopathy	2018-07-26	criteria provided, single submitter	clinical testing
Invitae	RCV001202590	SCV001373706	uncertain significance	Hypertrophic cardiomyopathy	2023-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1417 of the MYH7 protein (p.Thr1417Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 25351510). ClinVar contains an entry for this variant (Variation ID: 392176). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYH7 protein function with a positive predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002328998	SCV002632897	uncertain significance	Cardiovascular phenotype	2021-05-07	criteria provided, single submitter	clinical testing	The p.T1417I variant (also known as c.4250C>T), located in coding exon 29 of the MYH7 gene, results from a C to T substitution at nucleotide position 4250. The threonine at codon 1417 is replaced by isoleucine, an amino acid with similar properties. This alteration has been reported in a hypertrophic cardiomyopathy (HCM) cohort; however, clinical details were limited (Lopes LR et al. Heart, 2015 Feb;101:294-301). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV001170994	SCV004356813	uncertain significance	Cardiomyopathy	2023-03-16	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 1417 of the MYH7 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 an individual affected with hypertrophic cardiomyopathy (PMID: 25351510). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.