Submissions for variant NM_000257.4(MYH7):c.341T>C (p.Ile114Thr)

dbSNP: rs730880833

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cardiomyopathy Variant Curation Expert Panel	RCV000543876	SCV002041489	uncertain significance	Hypertrophic cardiomyopathy	2021-03-31	reviewed by expert panel	curation	The NM_000257.4(MYH7):c.341T>C (p.Ile114Thr) variant has been identified in 4 individuals with HCM (PS4_Supporting; Restrepo-Cordoba 2017 PMID:28138913; GeneDx pers. comm.; Invitae pers. comm.). This variant has also been identified in 1 individual with DCM who also carried a truncating variant in TTN and an individual with heart disease and sensory disfunction (Ambry pers. comm.; LMM pers. comm.). This variant was identified in 0.0009% (1/113612) of European chromosomes by gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, due to insufficient evidence, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Supporting, PM2, PP3.
GeneDx	RCV000158728	SCV000208663	uncertain significance	not provided	2020-01-31	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 28138913, 21310275)
Invitae	RCV000543876	SCV000623697	uncertain significance	Hypertrophic cardiomyopathy	2023-11-14	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 114 of the MYH7 protein (p.Ile114Thr). This variant is present in population databases (rs730880833, gnomAD 0.0009%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 28138913). ClinVar contains an entry for this variant (Variation ID: 181300). 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825644	SCV000967014	uncertain significance	not specified	2018-03-15	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Ile114Thr variant in MYH7 has been reported in 1 individual with HCM (Restrepo-Cordoba 20 17). It has also been identified in 1/111556 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs73088083 3). This variant was predicted to be pathogenic using a computational tool clini cally validated by our laboratory. This tool's pathogenic prediction is estimate d to be correct 94% of the time (Jordan 2011). In summary, while there is some s uspicion for a pathogenic role, the clinical significance of the p.Ile114Thr var iant is uncertain. ACMG/AMP Criteria applied: PM2; PP3.
Color Diagnostics, LLC DBA Color Health	RCV001524837	SCV001734799	uncertain significance	Cardiomyopathy	2020-08-17	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 114 of the MYH7 protein. Computational prediction suggests that this variant may have 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: 28138913). This variant has been identified in 1/251332 chromosomes 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.
Ambry Genetics	RCV002453549	SCV002614328	uncertain significance	Cardiovascular phenotype	2020-02-11	criteria provided, single submitter	clinical testing	The p.I114T variant (also known as c.341T>C), located in coding exon 2 of the MYH7 gene, results from a T to C substitution at nucleotide position 341. The isoleucine at codon 114 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in a hypertrophic cardiomyopathy (HCM) cohort (Alejandra Restrepo-Cordoba M et al. J Cardiovasc Transl Res, 2017 Feb;10:35-46). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002492628	SCV002780232	uncertain significance	Hypertrophic cardiomyopathy 1; Myopathy, myosin storage, autosomal recessive; Myosin storage myopathy; Congenital myopathy with fiber type disproportion; Dilated cardiomyopathy 1S; MYH7-related skeletal myopathy	2021-07-20	criteria provided, single submitter	clinical testing