Submissions for variant NM_000257.4(MYH7):c.2207T>C (p.Ile736Thr)

dbSNP: rs727503261

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cardiomyopathy Variant Curation Expert Panel	RCV000471476	SCV000564426	pathogenic	Hypertrophic cardiomyopathy	2016-12-15	reviewed by expert panel	curation	The c.2207T>C (p.Ile736Thr) variant in MYH7 has been reported in >20 individuals with hypertrophic cardiomyopathy (PS4; PMID:16630449; PMID:12974739; PMID:16199542; PMID:15856146; PMID:17125710; PMID:20738943; SHaRe consortium, PMID: 30297972; Partners LMM ClinVar SCV000199207.4; AGCMC Sydney ClinVar SCV000212631.2). This variant segregated with disease in 5 affected individuals (PP1_Moderate; PMID:15856146; PMID:17125710; Partners LMM ClinVar SCV000199207.4). This variant was absent from large population studies (PM2; http://exac.broadinstitute.org). 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; PMID:27532257). In summary, this variant meets criteria to be classified as pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4; PM1; PM2; PP1_Moderate
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000471476	SCV000199207	pathogenic	Hypertrophic cardiomyopathy	2016-02-16	criteria provided, single submitter	clinical testing	The p.Ile736Thr variant in MYH7 has been reported in >10 individuals with HCM, s egregated with disease in 7 affected relatives from 3 families (Erdman 2003, Ing les 2005, Liu 2006, Laredo 2006, Barriales Villa 2010, LMM data), and was absent from large population studies. In vitro functional studies provide some evidenc e that the p.Ile736Thr variant may not impact protein function (Seebohm 2009, Tr ipathi 2011). However, these types of assays may not accurately represent biolog ical function. Computational prediction tools and conservation analysis do not p rovide strong support for or against an impact to the protein. In summary, this variant meets our criteria to be classified as pathogenic for HCM in an autosoma l dominant manner based upon segregation studies and absence from controls.
GeneDx	RCV000158520	SCV000208455	pathogenic	not provided	2023-05-31	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; This variant is associated with the following publications: (PMID: 22112859, 8533830, 12974739, 19651039, 27247418, 28606303, 27532257, 15856146, 16199542, 23711808, 12820698, 17125710, 22455086, 25935763, 25346696, 26743238, 27217341, 21943931, 21472310, 21769673, 29398688, 29300372, 16630449, 19808356, 20738943, 20800588, 30775854, 31960626, 23074333, 29961767, 31513939, 33673806, 32894683, 33906374, 34542152, 35352813, 35626289, 35208637)
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV000151279	SCV000212631	pathogenic	Hypertrophic cardiomyopathy 1	2017-03-28	criteria provided, single submitter	research	This MYH7 Ile736Thr variant has been identified in multiple unrelated HCM individuals (see literature) and has been found to segregate in at least 2 families (Perrot A, et al., 2005; Laredo R, et al., 2007). The Ile736Thr variant occurs in the converter domain of the MYH7 which is generally associated with poorer outcomes in cardiomyopathy patients, however patients carrying this specific mutation were found to have less adverse events (García-Giustiniani D, et al., 2015). We have identified this variant in two HCM index cases in our patient cohort. The variant is absent from the 1000 genomes project (http://www.1000genomes.org/), as well as the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). Computational tools SIFT, PolyPhen-2 and MutationTaster predict the variant to be deleterious, however PolyPhen-HCM predicts this variant to be "benign". Based on multiple reports of the variant in HCM cases, strong segregation with disease, rarity in the general population and because missense MYH7 variants are a common cause of disease and rarely benign, we classify MYH7 Ile736Thr as "pathogenic".
Invitae	RCV000471476	SCV000546211	pathogenic	Hypertrophic cardiomyopathy	2024-01-17	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 736 of the MYH7 protein (p.Ile736Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 12820698, 12974739, 15856146, 16199542, 22112859, 22455086, 23711808, 25935763). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 164342). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on MYH7 function (PMID: 19651039, 25346696). For these reasons, this variant has been classified as Pathogenic.
Phosphorus, Inc.	RCV000151279	SCV000679783	pathogenic	Hypertrophic cardiomyopathy 1	2017-08-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000621605	SCV000740183	pathogenic	Cardiovascular phenotype	2020-08-28	criteria provided, single submitter	clinical testing	The p.I736T pathogenic mutation (also known as c.2207T>C), located in coding exon 18 of the MYH7 gene, results from a T to C substitution at nucleotide position 2207. The isoleucine at codon 736 is replaced by threonine, an amino acid with similar properties. This amino acid position is located within the converter domain of cardiac b-myosin, which is enriched in HCM-associated pathogenic variants (Homburger JR et al. Proc. Natl. Acad. Sci. U.S.A., 2016 06;113:6701-6). This variant has been detected in multiple individuals with hypertrophic cardiomyopathy from various ethnic groups (Erdmann J et al. Clin. Genet., 2003 Oct;64:339-49; Mohiddin SA et al. Genet. Test., 2003;7:21-7; Perrot A et al. J. Mol. Med., 2005 Jun;83:468-77; Ingles J et al. J. Med. Genet., 2005 Oct;42:e59; Liu WL et al. Zhonghua Xin Xue Guan Bing Za Zhi, 2006 Mar;34:202-7; Laredo R et al. Rev Esp Cardiol, 2006 Oct;59:1008-18; García-Giustiniani D et al. Heart, 2015 Jul;101:1047-53; Curila K et al. Acta Cardiol, 2012 Feb;67:23-9; Homburger JR et al. Proc. Natl. Acad. Sci. U.S.A., 2016 06;113:6701-6; Walsh R et al. Genet. Med., 2017 Feb;19:192-203). This variant has also been reported to segregate with disease in families (Perrot A et al. J. Mol. Med., 2005 Jun;83:468-77; Liu WL et al. Zhonghua Xin Xue Guan Bing Za Zhi, 2006 Mar;34:202-7; Laredo R et al. Rev Esp Cardiol, 2006 Oct;59:1008-18). In addition, the variant was suggested to reduce both mRNA and protein expression (Tripathi S et al. Basic Res. Cardiol., 2011 Nov;106:1041-55). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD), and is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Center for Human Genetics, University of Leuven	RCV000471476	SCV000886787	likely pathogenic	Hypertrophic cardiomyopathy	2018-10-31	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000158520	SCV000927206	pathogenic	not provided	2017-03-14	criteria provided, single submitter	clinical testing
KTest Genetics, KTest	RCV001594383	SCV001499970	pathogenic	Dilated cardiomyopathy 1S		criteria provided, single submitter	clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000151279	SCV001754771	pathogenic	Hypertrophic cardiomyopathy 1	2020-03-19	criteria provided, single submitter	clinical testing	The c.2207T>C (p.Ile736Thr) variant of MYH7 gene results in an amino acid change at residue 736 from an isoleucine to a threonine. This variant has been reported in multiple individuals with hypertrophic cardiomyopathy (PMID: 16199542, 22112859, 23711808, 12820698, 12974739, 22455086, 27247418; 27532257). This variant segregated with disease in affected individuals (PMID: 15856146, 25935763, 17125710). This change is predicted to be deleterious by multiple in-silico algorithms and has not been observed in the gnomAD population variant database. Furthermore, this variant lies in a functionally important domain where other cardiomyopathy-associated missense variants have been described (PMID: 27532257). For these reasons, this variant c.2207T>C (p.Ile736Thr) variant in MYH7 is interpreted as pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149921	SCV003838759	pathogenic	Cardiomyopathy	2021-09-24	criteria provided, single submitter	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000158520	SCV000280316	likely pathogenic	not provided	2012-01-31	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p. Ile736Thr (c.2207 T>C) in the MYH7 gene. The patient's genetic test results were last reviewed in September 2011. They were re-reviewed April 17th, 2013. There was no new case data on the variant, however there was new data on its prevalence in the general population. This variant has been reported in at least 9 unrelated cases with HCM (not including the patient) with weak segregation data (Mohiddin et al 2003; Perrot et al 2005; Ingles et al 2005; Liu et al 2006). Perrot et al (2005) reported the variant in three family members with HCM. Laredo et al (2006) reported the variant in three unrelated families with HCM; in one family the variant was observed in three affected individuals. We have seen the variant in another family with HCM. Other variants at the same codon have been reported in association with HCM: p.Ile736Val (Gorham et al 2003) and p.Ile736Met (Koyangi et al 1996, Muraishi et al 1999). Krischner et al (2005) reported the p.Ile736Thr is associated with a slightly increased calcium sensitivity and higher active forces at lower calcium concentrations with residual active force under relaxing conditions. PolyPhen-2 predicts the variant to be probably damaging (with a score of 1.00). The isoleucine at codon 736 is completely conserved across species and neighboring amino acids are either completely or highly conserved. In total the variant has not been seen in ~6996 published controls and individuals from publicly available population datasets. There is no variation at codon 736 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of April 17th, 2013). There is also no variation at this codon listed in dbSNP (as of April 17th, 2013). There is a variant at codon 736 listed in 1000 genomes, however that points to an HGMD entry (April 17th, 2013). The variant was not observed in the following published control samples: The p.Ile736Thr variant has been reported as absent in 96 (Perrot et al 2005), 100 (Mohiddin et al 2003), 100 (Laredo et al 2006), 150 (Ingles et al 2005), and 50 (Erdmann et al 2003) individuals for a total of 496 presumed healthy individuals.
Institute of Human Genetics, University of Wuerzburg	RCV000151279	SCV004032152	pathogenic	Hypertrophic cardiomyopathy 1		no assertion criteria provided	clinical testing