Submissions for variant NM_000257.4(MYH7):c.1370T>C (p.Ile457Thr)

gnomAD frequency: 0.00001  dbSNP: rs397516103

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cardiomyopathy Variant Curation Expert Panel	RCV000477379	SCV001976469	likely pathogenic	Hypertrophic cardiomyopathy	2021-09-22	reviewed by expert panel	curation	The c.1370T>C (p.Ile457Thr) variant in MYH7 has been identified in >20 individuals with HCM (PS4_Strong; Waldmüller 2011 PMID: 21750094; Fokstuen 2011 PMID: 21239446; Helms 2016: 27688314; Homburger 2016 PMID: 27247418; Murphy 2016 PMID: 26914223; Ingles 2017 PMID: 28408708; Ross 2017 PMID: 28615295; Viswanathan 2017 PMID: 29121657; Walsh 2017 PMID:27532257; Ko 2018 PMID: 28640247; Centenary Institute Sydney pers. comm.; GeneDx pers. comm., Invitae pers. comm.; LMM pers. comm.; OGML pers. comm.). This variant also segregated with HCM in 1 affected relative (GeneDx pers. comm.); however, this data is currently insufficient to establish co-segregation with disease and apply PP1. Additionally, this variant has also been reported in 1 individual with left bundle branch block, 1 individual with sudden cardiac arrest (who carried additional variants in other cardiomyopathy associated genes) and 1 individual with myopathy who also had additional variants in myopathy-associated genes and segregated with myopathy in one affected relative (Ambry pers. comm.; CHEO pers. comm.; Invitae pers. comm.). This variant has also been identified in 0.0009% (1/113764) of European chromosomes by gnomAD v2.1.1 (PM2; http://gnomad.broadinstitute.org). In vitro functional studies provide some evidence that this variant could impact protein function (Adhikari 2019 PMID: 31213605); however, this data is currently insufficient to establish functional impact and apply PS3. This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4; PM2; PM1; PP3.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000477379	SCV000059371	likely pathogenic	Hypertrophic cardiomyopathy	2019-08-29	criteria provided, single submitter	clinical testing	The p.Ile457Thr variant in MYH7 has been reported in at least 10 individuals with HCM (Waldmüller 2011, Fokstuen 2011, Murphy 2016, Walsh 2016, Viswanathan 2017, LMM data). This variant has been identified in 1/113764 European chromosomes by gnomAD (http://gnomad.broadinstitute.org/). This variant has been reported in ClinVar (Variant ID: 42840). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Of note, this variant lies in the head region of the protein and missense variants in this region are statistically more likely to be disease-associated (Walsh 2016). 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: PM1, PM2, PS4_Moderate, PP3.
GeneDx	RCV000035720	SCV000208736	likely pathogenic	not provided	2023-03-17	criteria provided, single submitter	clinical testing	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; Published functional studies suggest a damaging effect: increased ATPase activity and actin gliding velocity leading to hypercontractility (Adhikari et al., 2019); This variant is associated with the following publications: (PMID: 27532257, 21750094, 27247418, 26914223, 21239446, 28615295, 28408708, 28790153, 29121657, 31447099, 34330286, 31068177, 29300372, Morck2021[Preprint], 27688314, 32894683, 31213605, 28606303, 28640247, 25125180, 30767072)
Invitae	RCV000477379	SCV000546249	pathogenic	Hypertrophic cardiomyopathy	2023-11-17	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 457 of the MYH7 protein (p.Ile457Thr). This variant is present in population databases (rs397516103, gnomAD 0.0009%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 21750094, 26914223, 27247418, 27532257, 27688314, 28615295, 29121657; Invitae). ClinVar contains an entry for this variant (Variation ID: 42840). 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%. Experimental studies have shown that this missense change affects MYH7 function (PMID: 31213605). This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000617592	SCV000736144	likely pathogenic	Cardiovascular phenotype	2023-05-30	criteria provided, single submitter	clinical testing	The p.I457T variant (also known as c.1370T>C), located in coding exon 12 of the MYH7 gene, results from a T to C substitution at nucleotide position 1370. The isoleucine at codon 457 is replaced by threonine, an amino acid with similar properties. This alteration is located in the myosin head domain, which contains a statistically significant clustering of pathogenic missense variants (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6; Walsh R et al. Genet Med, 2017 02;19:192-203; Ambry internal data).This variant has been reported in numerous hypertrophic cardiomyopathy cohorts (Waldmüller S et al. Eur. J. Heart Fail., 2011 Nov;13:1185-92; Fokstuen S et al. J. Med. Genet., 2011 Aug;48:572-6; Helms AS et al. Circulation, 2016 Nov;134:1738-1748; Homburger JR et al. Proc. Natl. Acad. Sci. U.S.A., 2016 06;113:6701-6; Ross SB et al. Circ Cardiovasc Genet, 2017 Jun;10; Viswanathan SK et al. PLoS ONE, 2017 Dec;12:e0187948; Walsh R et al. Genet. Med., 2017 02;19:192-203; Ko C et al. Genet. Med., 2018 01;20:69-75; GeneDx pers comm; Invitae pers comm). In one study, this variant was reported to impact protein function (Adhikari AS et al. Nat Commun. 2019 06;10(1):2685). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV000477379	SCV000996339	likely pathogenic	Hypertrophic cardiomyopathy	2017-03-21	criteria provided, single submitter	research	This MYH7 Ile457Thr variant has been previously described in the literature in 9 HCM patients (Waldmuller S, et al., 2011; Fokstuen S, et al., 2011; Helms As, et al., 2016; Walsh et al., 2017). It is present in the Exome Aggregation Consortium dataset (MAF=0.000008; http://exac.broadinstitute.org/) as a singleton event. We have identified MYH7 Ile457Thr in 1 HCM proband with no established family history of disease. In silico tools and conservation scores support a deleterious role (SIFT "Deleterious"; PolyPhen-2 "Probably-damaging"; PolyPhen-HCM "Pathogenic"; MutationTaster "Disease-causing"). In a large HCM population study Walsh et al., showed that MYH7 variants identified in HCM cases were found to cluster between amino acids 181- 937 (2017), this implies that variants in this region are likely to cause a HCM phenotype. Based on this evidence, we classify MYH7 Ile457Thr as "likely pathogenic".
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV001258094	SCV001434938	likely pathogenic	Hypertrophic cardiomyopathy 1	2018-10-14	criteria provided, single submitter	clinical testing	The c.1324C>T (p.Arg442Cys) variant in the MYH7 gene has been reported in multiple unrelated patients affected with hypertrophic cardiomyopathy (PMID 21239446, 21750094, 26914223, 27247418, 27532257) and is extremely rare in general population databases. This variant is located in the critical myosin head domain of MYH7 and is predicted to be damaging by multiple in silico algorithms. Therefore, this c.1324C>T (p.Arg442Cys) variant in the MYH7 gene is classified as likely pathogenic. [yunyun, 2018-10-14]
Color Diagnostics, LLC DBA Color Health	RCV001804758	SCV002051892	likely pathogenic	Cardiomyopathy	2023-12-05	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 457 of the MYH7 protein. This variant is found within a highly conserved region of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. In vitro functional experiments have shown that this variant increases actin-activated ATPase kinetics and actin gliding velocity (PMID: 31213605). This variant has been reported in over ten individuals affected with hypertrophic cardiomyopathy (PMID: 21239446, 21750094, 26914223, 27247418, 27688314, 28615295, 28790153, 29121657, 32894683, 35026164), and in one individual affected with myosin storage myopathy with a combination of skeletal, respiratory, and cardiac muscle involvement (PMID: 31068177). This variant has been identified in 1/251490 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002496539	SCV002807213	likely pathogenic	Hypertrophic cardiomyopathy 1; Myopathy, myosin storage, autosomal recessive; Myosin storage myopathy; Congenital myopathy with fiber type disproportion; Dilated cardiomyopathy 1S; MYH7-related skeletal myopathy	2021-11-10	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000035720	SCV003817719	uncertain significance	not provided	2020-10-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003478982	SCV004222732	likely pathogenic	Primary familial hypertrophic cardiomyopathy	2023-11-16	criteria provided, single submitter	clinical testing	Variant summary: MYH7 c.1370T>C (p.Ile457Thr) results in a non-conservative amino acid change located in the Myosin head, motor domain (IPR001609) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251490 control chromosomes. c.1370T>C has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (e.g. Waldmuller_2011, Helms_2016) including in settings of multi-gene panel testing with frequent classification as likely pathogenic (e.g. Fokstuen_2011, Ingles_2017, Ross_2017, Ho_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 21239446, 27688314, 30297972, 28408708, 28615295, 21750094). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as pathogenic (n=1), likely pathogenic (n=8), or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000035720	SCV004702863	likely pathogenic	not provided	2024-02-01	criteria provided, single submitter	clinical testing	MYH7: PM2, PS4:Moderate, PP3, PS3:Supporting