ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.2207T>C (p.Ile736Thr) (rs727503261)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Inherited 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, Partners HealthCare 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 2019-03-22 criteria provided, single submitter clinical testing The I736T pathogenic variant in the MYH7 gene has been reported in multiple individuals with HCM, across various ethnicities (Erdmann et al., 2003; Mohiddin et al., 2003; Ingles et al., 2005; Perrot et al., 2005; Laredo et al., 2006; Curila et al., 2012; Otsuka et al., 2012; Pan et al., 2012; Liu et al., 2013; Garcia- Giustiniani et al., 2015; Homburger et al., 2016; Walsh et al., 2017). I736T also been observed in multiple individuals referred for HCM genetic testing at GeneDx. Segregation with HCM has been clearly demonstrated in multiple unrelated families, as reported in published literature (Perrot et al., 2005; Laredo et al., 2006) and observed at GeneDx. This variant is also not observed in large population cohorts (Lek et al., 2016).
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000151279 SCV000212631 pathogenic Familial 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 2018-10-11 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 736 of the MYH7 protein (p.Ile736Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature segregating with hypertrophic cardiomyopathy (HCM) in several families (PMID: 15856146, 25935763), as well as in multiple unrelated individuals affected with HCM (PMID: 16199542, 22112859, 23711808, 12820698, 12974739, 22455086). Experimental studies have shown that this missense change causes incomplete relaxation compared to control fibers at the same calcium levels (PMID: 25346696). Different experimental studies found no effect on resistance to elastic distortion (PMID: 19651039). However, the clinical significance of these experiments is uncertain. In summary, this variant is a rare missense change that is absent in the general population, it has been reported in multiple unrelated affected individuals and has been shown to segregate with disease in multiple families. For these reasons, this variant has been classified as Pathogenic.
Phosphorus, Inc. RCV000151279 SCV000679783 pathogenic Familial hypertrophic cardiomyopathy 1 2017-08-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000621605 SCV000740183 likely pathogenic Cardiovascular phenotype 2017-06-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Good segregation with disease (lod 1.5-3 = 5-9 meioses),Rarity in general population databases (dbsnp, esp, 1000 genomes)
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
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.

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