ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.715G>A (p.Asp239Asn) (rs397516264)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000628940 SCV000059647 pathogenic Hypertrophic cardiomyopathy 2015-09-10 criteria provided, single submitter clinical testing The p.Asp239Asn variant in MYH7 has been identified in 7 individuals with HCM an d segregated with disease in 5 affected relatives (Iascone 2007, Kaski 2009, Gar cia-Pavia 2011, LMM unpublished data). This variant was absent from large popula tion studies. Aspartic acid (Asp) at position 239 is highly conserved in mammals and across evolutionarily distant species and the change to asparagine (Asn) wa s predicted to be pathogenic 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, this variant meets our criteria to be cl assified as pathogenic for HCM in an autosomal dominant manner (http://www.partn ers.org/personalizedmedicine/LMM) based upon segregation studies, absence from c ontrols, and predicted impact to the protein.
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000162339 SCV000212639 likely pathogenic Familial hypertrophic cardiomyopathy 1 2014-12-01 criteria provided, single submitter research This MYH7 Asp139Asn variant has previously been described in the literature in HCM cases (Kaski JP, et al., 2009; Iascone MR, et al., 2007). Both of the HCM individuals described were diagnosed at a young age, and segregation analysis by Iascone MR, et al. (2007) also identified the same MYH7 Asp239Asn variant in the proband's affected mother. This variant is absent in general population databases including 1000 genomes project (http://www.1000genomes.org/), and the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). Aspartic acid at position 239 is highly conserved across distantly related species, and computational tools predict the Asp239Asn to be "deleterious" (SIFT) and "disease-causing" (MutationTaster). Additionally, a tool specifically designed to predict the effects of missense variants in HCM genes (Jordan DM, et al., 2011), predicts that this MYH7 Asp239Asn variant is causative of the disease. Based on the current literature, absence of this variant in population datasets, its occurrence in a highly conserved region, and the prediction of in silico models, we classify this variant as "likely pathogenic". Further supporting evidence such as strong segregation data and/or functional analysis will be required to clarify its clinical significance.
Ambry Genetics RCV000622036 SCV000740109 likely pathogenic Cardiovascular phenotype 2017-01-23 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,Rarity in general population databases (dbsnp, esp, 1000 genomes),Moderate segregation with disease (at least 3 informative meioses) for rare diseases.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000035995 SCV000747985 likely pathogenic Primary familial hypertrophic cardiomyopathy 2017-06-27 criteria provided, single submitter clinical testing
Invitae RCV000628940 SCV000749848 pathogenic Hypertrophic cardiomyopathy 2018-06-25 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 239 of the MYH7 protein (p.Asp239Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in several individuals affected with hypertrophic cardiomyopathy (PMID: 26914223, 20031618, 21896538, 27247418, 27532257), and in an individual affected with inherited arrhythmia (PMID: 26743238). ClinVar contains an entry for this variant (Variation ID: 43100). 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). Experimental in-vitro motility studies showed that this variant affected several aspects of protein function, resulting in a significantly elevated velocity (PMID: 27974200). In summary, this variant is a rare missense change that has been reported in several affected individuals and has been shown to affect protein function. For these reasons it has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000762926 SCV000893344 likely pathogenic Familial hypertrophic cardiomyopathy 1; Myopathy, myosin storage, autosomal recessive; Myosin storage myopathy; Congenital myopathy with fiber type disproportion; Dilated cardiomyopathy 1S; Myopathy, distal, 1; Scapuloperoneal myopathy, MYH7-related 2018-10-31 criteria provided, single submitter clinical testing

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