ClinVar Miner

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

dbSNP: rs397516264
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Cardiomyopathy Variant Curation Expert Panel RCV000628940 SCV001842656 likely pathogenic Hypertrophic cardiomyopathy 2021-03-22 reviewed by expert panel curation The c.715G>A (p.Asp239Asn) variant in MYH7 has been identified in at least 13 individuals with HCM (PS4_Moderate; Iascone 2007 PMID:17438619; Kaski 2009 PMID:20031618; Garcia-Pavia 2011 PMID:21896538; Murphy 2016 PMID:26914223; Homburger 2016 PMID:27247418; Walsh 2017 PMID:27532257; Ingles 2017 PMID:28408708) and segregated with HCM in 5 affected individuals from 4 families (PP1_Moderate; Iascone 2007 PMID:17438619; Garcia-Pavia 2011 PMID:21896538; LMM ClinVar SCV000059647.6 and pers comm). This variant has been identified in 0.003% (1/34592) of Latino chromosomes but is absent from all other populations in gnomAD v2.1.1 (PM2; http://gnomad.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; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis were mixed about the potential impact of this variant. In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Moderate; PP1_Moderate; PM2; PM1
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000628940 SCV000059647 pathogenic Hypertrophic cardiomyopathy 2023-11-14 criteria provided, single submitter clinical testing The p.Asp239Asn variant in MYH7 has been identified in at least 15 individuals with hypertrophic cardiomyopathy (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, v.2.1.1). 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). Additionally, this variant was classified as likely pathogenic by the ClinGen-approved cardiomyopathy variant curation expert panel (Variation ID: 43100). 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 2024-01-21 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 239 of the MYH7 protein (p.Asp239Asn). This variant is present in population databases (rs397516264, gnomAD 0.003%). This missense change has been observed in individuals with inherited arrhythmia and hypertrophic cardiomyopathy (PMID: 20031618, 21896538, 26743238, 26914223, 27247418, 27532257). ClinVar contains an entry for this variant (Variation ID: 43100). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYH7 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MYH7 function (PMID: 27974200). 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.
Fulgent Genetics, Fulgent Genetics RCV000762926 SCV000893344 likely pathogenic Hypertrophic cardiomyopathy 1; Myopathy, myosin storage, autosomal recessive; Myosin storage myopathy; Congenital myopathy with fiber type disproportion; Dilated cardiomyopathy 1S; MYH7-related skeletal myopathy 2018-10-31 criteria provided, single submitter clinical testing
Mendelics RCV000162339 SCV001139419 likely pathogenic 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 2020-02-14 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV001170745 SCV001343926 likely pathogenic Cardiomyopathy 2019-10-18 criteria provided, single submitter clinical testing This missense variant replaces aspartic acid with asparagine at codon 239 of the MYH7 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. A functional study has shown that this variant affects the protein normal function by significantly increases actin-activated ATPase activity and actin gliding velocities compared to the wild type protein (PMID: 27974200). This variant has been reported in over ten individuals affected with hypertrophic cardiomyopathy (PMID: 20031618, 21896538, 26914223, 27247418, 27532257, 28138913, Color internal data) and arrhythmia (PMID: 26743238). This variant has been identified in 1/251496 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
3billion RCV000162339 SCV002058127 likely pathogenic Hypertrophic cardiomyopathy 1 2022-01-03 criteria provided, single submitter clinical testing Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000043100, PMID:NULL, PS1_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.663, 3CNET: 0.986, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000004, PM2_M). The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.

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