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

dbSNP: rs397516264

Total submissions: 11

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	2024-04-15	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. 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). This alteration is located in the myosin head domain, which contains a statistically significant clustering of pathogenic missense variants (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6; Walsh R et al. Genet Med, 2017 02;19:192-203; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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
Labcorp Genetics (formerly Invitae), Labcorp	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.