ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.5287G>A (p.Ala1763Thr) (rs727504355)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000154483 SCV000204153 uncertain significance not specified 2017-07-12 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Ala1763Th r variant in MYH7 has been reported in 1 infant with HCM, who also carried a pat hogenic variant in MYBC3, and 6 individuals with cardiomyopathy (5 with HCM, and 1 with DCM: Berge 2014, Bos 2014, Alfares 2015, Walsh 2017, LMM data). One of t he individuals with HCM carried an additional pathogenic variant in MYH7 suffici ent to explain their disease. This variant has also been identified in 14/126724 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad. broadinstitute.org; dbSNP rs727504355). This variant was predicted to be pathoge nic using a computational tool clinically validated by our laboratory. This tool 's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011 ). In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Ala1763Thr variant is uncertain.
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000464078 SCV000223881 uncertain significance Hypertrophic cardiomyopathy 2018-11-27 criteria provided, single submitter research The Ala1763Thr variant has been previously reported in 4 SUD cases (Dewar LJ et al., 2017), 3 DCM cases (Broch K, et al., 2018; LMM, Pers. Comm.; Phosphorus inc, ClinVar SCV000679791), 1 LVNC case (Blueprint, ClinVar SCV000264098), 3 myopathy cases (Phosphorus inc, ClinVar SCV000679793-5) and 7 HCM cases (Walsh et al., 2017; Cecconi M, et al., 2016; Bos JM, et al., 2014; Berge & Leren, 2014; Invitae, ClinVar SCV000546187; Phosphorus inc, ClinVar SCV000679792). It is present at an elevated frequency of 0.0000685 in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). The MYH7 Ala1736Thr variant occurs in a conserved region, and in silico tools (SIFT, PolyPhen2, MutationTaster and CADD) support a damaging role for this variant. We have identified this variant in a single HCM proband who has no family history of disease (Ingles J et al., 2017; Burns C, et al., 2017). Based on the adapted ACMG guidelines (Kelly MA, et al., 2018), this variant is not rare in the general population and therefore probands cannot be counted as evidence. In silico tools predict it to deleterious (PP3), therefore we classify MYH7 Ala1763Thr as a variant of 'uncertain significance'.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000724585 SCV000229809 uncertain significance not provided 2015-03-05 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000208237 SCV000264098 uncertain significance Left ventricular noncompaction cardiomyopathy 2014-12-16 criteria provided, single submitter clinical testing
Invitae RCV000464078 SCV000546187 uncertain significance Hypertrophic cardiomyopathy 2019-12-31 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 1763 of the MYH7 protein (p.Ala1763Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs727504355, ExAC 0.007%). This variant has been reported in individuals with hypertrophic cardiomyopathy (PMID: 24111713, 25611685, 24793961, 28790153, 27532257, 27600940), one individual with dilated cardiomyopathy (PMID: 26468400) and individuals affected with sudden unexplained death (PMID: 28807990). ClinVar contains an entry for this variant (Variation ID: 177846). 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"). 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.
Phosphorus, Inc. RCV000578112 SCV000679791 uncertain significance Dilated cardiomyopathy 1S 2017-08-01 criteria provided, single submitter clinical testing
Phosphorus, Inc. RCV000172890 SCV000679792 uncertain significance Familial hypertrophic cardiomyopathy 1 2017-08-01 criteria provided, single submitter clinical testing
Phosphorus, Inc. RCV000578027 SCV000679793 uncertain significance Myopathy, distal, 1 2017-08-01 criteria provided, single submitter clinical testing
Phosphorus, Inc. RCV000578110 SCV000679794 uncertain significance Myosin storage myopathy 2017-08-01 criteria provided, single submitter clinical testing
Phosphorus, Inc. RCV000577993 SCV000679795 uncertain significance Myopathy, myosin storage, autosomal recessive 2017-08-01 criteria provided, single submitter clinical testing
Center for Human Genetics,University of Leuven RCV000464078 SCV000886838 uncertain significance Hypertrophic cardiomyopathy 2018-10-31 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769433 SCV000900826 uncertain significance Cardiomyopathy 2019-04-17 criteria provided, single submitter clinical testing
Color RCV000769433 SCV001356062 uncertain significance Cardiomyopathy 2019-08-02 criteria provided, single submitter clinical testing

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