ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.788T>C (p.Ile263Thr) (rs397516269)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Cardiomyopathy Variant Curation Expert Panel RCV000758021 SCV000564409 pathogenic Hypertrophic cardiomyopathy 2016-12-15 reviewed by expert panel curation The c.788T>C (p.Ile263Thr) variant in MYH7 has been reported in >20 individuals with hypertrophic cardiomyopathy (PS4: PMID:15008060; PMID:9829907; PMID:12707239; PMID:22429680; PMID:20624503; Partners LMM ClinVar SCV000059656.5; SHaRe consortium, PMID: 30297972). This variant segregated with disease in 10 affected individuals (PP1_Strong: PMID:15008060; PMID:9829907). This variant was absent from large population studies (PM2; 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). 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 pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4, PP1_Strong, PM1, PM2, PP3
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000758021 SCV000059656 pathogenic Hypertrophic cardiomyopathy 2013-04-09 criteria provided, single submitter clinical testing The Ile263Thr variant in MYH7 has been reported in 7 individuals with HCM and se gregated with disease in >10 affected relatives (Tesson 1997, Tesson 1998, Brito 2003, Richard 2003, Brito 2005, Santos 2012). This variant was not identified i n large population studies. Isoleucine (Ile) at position is highly conserved in mammals and across evolutionarily distant species and the change to threonine (T hr) was predicted to be pathogenic using a computational tool clinically validat ed by our laboratory. This tool's pathogenic prediction is estimated to be corre ct 94% of the time (Jordan 2011). In summary, this variant meets our criteria to be classified as pathogenic ( based upon segregat ion studies and absence from controls.
GeneDx RCV000158766 SCV000208701 pathogenic not provided 2020-06-29 criteria provided, single submitter clinical testing Reported in ClinVar as pathogenic by the ClinGen Inherited Cardiomyopathy Variant Curation Expert Panel (SCV000564409.4 ; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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: 9829907, 12707239, 27737317, 23074333, 21425739, 15008060, 16335287, 22429680, 24014347, 20624503, 22857948, 24093860, 9140839, 27532257, 27247418, 25937619, 29300372, 30297972, 31513939, 31589614, 33258288, 33586461)
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000201434 SCV000256142 likely pathogenic Familial hypertrophic cardiomyopathy 1 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000036004 SCV000747937 likely pathogenic Primary familial hypertrophic cardiomyopathy 2017-02-21 criteria provided, single submitter clinical testing
Center for Human Genetics,University of Leuven RCV000758021 SCV000886776 pathogenic Hypertrophic cardiomyopathy 2018-10-31 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769465 SCV000900860 likely pathogenic Cardiomyopathy 2016-04-12 criteria provided, single submitter clinical testing
Invitae RCV000758021 SCV000935029 pathogenic Hypertrophic cardiomyopathy 2020-02-20 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 263 of the MYH7 protein (p.Ile263Thr). 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 observed in individuals and families affected with hypertrophic cardiomyopathy (PMID: 9829907, 24093860, 27247418, 27532257, 21425739, 12707239, 15008060). ClinVar contains an entry for this variant (Variation ID: 43106). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). 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.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000158766 SCV000280380 likely pathogenic not provided 2015-06-23 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. MYH7 p.Ile263Thr (c.788T>C) The variant has been seen in at least 5 unrelated cases. The database curated by the Seidman group notes that the variant was first reported in an individual with HCM by Tesson et al (1997) but was mistakenly referred to as p.Ile263Trp ( The same group did later report a family with two affected members with "I263T", presumably the same family and variant (Tesson et al 1998). Richard et al (2003) reported one HCM patient with this variant in their French cohort. Brito et al (2003, 2005) reported the variant in multiple family members of two unrelated Portugese families. Unfortunately only the abstracts are available so we could not confirm details. Millat et al (2010) observed the variant in one individual with HCM in their French cohort (appears to be distinct from the Richard et al cohort). In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. The isoleucine at codon 263 is conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at this codon (p.Ile263Met, which we consider of uncertain significance, probably disease causing) and a nearby codon (p.Gly256Glu). In total the variant has not been seen in ~5700 published controls and publicly available population datasets. There is no variation at codon 263 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~5500 Caucasian and African American individuals (as of 1/16/2012). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 1/16/2012). The variant was not observed in the following published control samples: 100 (Tesson et al 1998), 100 (Richard et al 2003).

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