ClinVar Miner

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

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Total submissions: 9
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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 2021-02-24 criteria provided, single submitter clinical testing The p.Asp239Asn variant in MYH7 has been identified in at least 15 individuals with HCM and segregated with disease in 7 affected relatives (Iascone 2007 PMID: 17438619, Kaski 2009 PMID: 20031618, Garcia-Pavia 2011 PMID: 21896538, Homburger 2016 PMID: 27247418, Adler 2016 PMID: 26743238, Murphy 2016 PMID: 26914223, Walsh 2017 PMID: 27532257, Ross 2017 PMID: 28615295, LMM data). It has also been identified in 1/34592 of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). An in vitro functional study supports an impact on protein function (Adhikari 2016 PMID: 27974200). Of note, this variant lies in the head region of the protein and missense variants in this region are statistically more likely to be disease-associated (Walsh 2017 PMID: 27532257). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PS4, PM1, PM2_Supporting, PP1_Strong, PS3_Supporting.
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000628940 SCV000212639 pathogenic Hypertrophic cardiomyopathy 2019-02-04 criteria provided, single submitter research MYH7 Asp239Asn has been previously reported in multiple HCM cases (Walsh et al., 2017; Adler et al., 2016; Murphy et al., 2016; Garcia-Pavia et al., 2011; Kaski et al., 2009; Iascone et al., 2007) and has been found to segregate in their families (Garcia-Pavia et al., 2011; Ambry, ClinVar SCV000740109.2). We have also identified MYH7 Asp239Asn in a HCM proband (Ingles et al., 2017) as well as their 3 affected family members. This variant is present in the Genome Aggregation Database (http://gnomad.broadinstitute.org/) at an allele frequency of 0.000004. An in vitro functional study showed that the variant results in higher actin activated ATPase activity, higher actin gliding velocities and increased intrinsic force of the protein which results in hypercontractility (Adhikari et al., 2016). In a large HCM population study Walsh et al., showed that MYH7 variants identified in HCM cases were found to cluster between amino acids 181- 937 (2017), this implies that variants in this region are likely to cause a HCM phenotype. In silico tools PolyPhen2 and MutationTaster predict this variant to be deleterious, however SIFT predicts it to be "Tolerated". Based on the adapted ACMG criteria (Kelly MA, et al., 2018) this variant has been identified in at least 12 HCM probands without additional variants (PS4_moderate), shown to segregate strongly with disease across multiple families (PP1_Supporting), has been shown to have a damaging affect on protein in a functional study (PS3), it is located in a mutational hotspot (PM1) and is rare in the general population (PM2), therefore we classify MYH7 Asp239Asn as 'pathogenic'.
Ambry Genetics RCV000622036 SCV000740109 pathogenic Cardiovascular phenotype 2020-07-27 criteria provided, single submitter clinical testing The p.D239N pathogenic mutation (also known as c.715G>A), located in coding exon 6 of the MYH7 gene, results from a G to A substitution at nucleotide position 715. The aspartic acid at codon 239 is replaced by asparagine, an amino acid with highly similar properties, and is located in the head domain. This alteration has been reported in several individuals with hypertrophic cardiomyopathy (HCM), often characterized by an early age of onset (Homburger JR et al. Proc. Natl. Acad. Sci. U.S.A., 2016 06;113:6701-6; Kaski JP et al. Circ Cardiovasc Genet, 2009 Oct;2:436-41; Murphy SL et al. J Cardiovasc Transl Res, 2016 Apr;9:153-61; Garcia-Pavia P et al. Eur. J. Heart Fail., 2011 Nov;13:1193-201; Iascone MR et al. Hum. Genet., 2007 Feb;120:916; Ross SB et al. Circ Cardiovasc Genet, 2017 Jun;10; Adler A et al. Circ Arrhythm Electrophysiol, 2016 Jan;9:e003440; Alejandra Restrepo-Cordoba M et al. J Cardiovasc Transl Res, 2017 Feb;10:35-46; Ingles J et al. Circ Cardiovasc Genet, 2017 Apr;10; Norrish G et al. Circulation, 2019 07;140:184-192; Walsh R et al. Genet. Med., 2017 02;19:192-203). This alteration has been described to segregate with HCM in multiple families (Garcia-Pavia P et al. Eur. J. Heart Fail., 2011 Nov;13:1193-201; Iascone MR et al. Hum. Genet., 2007 Feb;120:916). Functional in vitro analyses have suggested this variant increases catalytic rate, velocity, and generation of force and therefore may adversely affect ventricular contraction (Adhikari AS et al. Cell Rep. 2016;17:2857-2864). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
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 2020-08-29 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; MYH7-related late-onset scapuloperoneal muscular dystrophy 2018-10-31 criteria provided, single submitter clinical testing
Mendelics RCV000162339 SCV001139419 likely pathogenic Familial hypertrophic cardiomyopathy 1 2019-05-28 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001170745 SCV001333350 pathogenic Cardiomyopathy 2018-02-16 criteria provided, single submitter clinical testing
Color Health, Inc RCV001170745 SCV001343926 likely pathogenic Cardiomyopathy 2019-10-18 criteria provided, single submitter clinical testing

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