ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.2717A>G (p.Asp906Gly) (rs267606908)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Inherited Cardiomyopathy Variant Curation Expert Panel, RCV000469895 SCV000564437 pathogenic Hypertrophic cardiomyopathy 2016-12-15 reviewed by expert panel curation The c.2717A>G (p.Asp906Gly) variant in MYH7 has been reported in >20 individuals with hypertrophic cardiomyopathy (PS4; PMID:27532257; PMID:12081993; PMID:15528230; PMID:16267253; PMID:24510615; Partners LMM ClinVar SCV000059468.5). This variant segregated with disease in 10 affected individuals (PP1_Strong; PMID:12081993; PMID:15528230). This variant was absent from large population studies (PM2; http://exac.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; PMID:27532257). In summary, this variant meets criteria to be classified as pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4; PP1_ Strong; PM1; PM2
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000469895 SCV000059468 pathogenic Hypertrophic cardiomyopathy 2017-11-28 criteria provided, single submitter clinical testing The p.Asp906Gly variant in MYH7 has been identified in >15 individuals with HCM and segregated with disease in >10 affected relatives from 2 families, although reduced penetrance was noted in both families (Ho 2002, Alpert 2005, Arad 2005, Kapplinger 2014, LMM data). It has been identified in 1/246244 of European chrom osomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute. org; dbSNP rs267606908). This low frequency is consistent with the prevalence an d penetrance of the condition in the general population. In vitro functional stu dies provide some evidence that the p.Asp906Gly variant may impact protein funct ion (Alpert 2005). In addition, the p.Asp906Gly variant was predicted to be path ogenic using a computational tool clinically validated by our laboratory. This t ool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2 011). In summary, this variant meets criteria to be classified as pathogenic for HCM in an autosomal dominant manner based upon segregation studies, low frequen cy in the general population and functional evidence. ACMG/AMP criteria applied: PS4, PM2, PP1_Strong, PP3.
GeneDx RCV000158569 SCV000208504 pathogenic not provided 2019-01-08 criteria provided, single submitter clinical testing The D906G pathogenic variant in the MYH7 gene has previously been reported in several individuals with HCM (Ho et al., 2002; Alpert et al., 2005; Arad et al., 2005; Miller et al., 2013; Kapplinger et al., 2014). Additionally, this variant was reported to segregate with HCM in ten relatives from two different families (Ho et al., 2002; Alpert et al., 2005). Furthermore, the D906G variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The D906G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Furthermore, this substitution occurs within the S2-segment of the myosin rod (Alpert et al., 2005), at a position where only amino acids with similar properties to aspartic acid are tolerated across species. Moreover, a functional study demonstrated that myosin, isolated from biceps muscle tissue from individuals heterozygous for the D906G variant, moved actin with an increased velocity compared to myosin isolated from control tissue (Alpert et al., 2005). Finally, several likely pathogenic/pathogenic missense variants in nearby residues (E903G, E903K, R904C, R904H, L908V) have been reported in the Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014), further supporting the functional importance of this region of the protein.
Blueprint Genetics RCV000035817 SCV000264085 pathogenic Primary familial hypertrophic cardiomyopathy 2015-11-10 criteria provided, single submitter clinical testing
Invitae RCV000469895 SCV000546214 pathogenic Hypertrophic cardiomyopathy 2019-12-20 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 906 of the MYH7 protein (p.Asp906Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is not present in population databases (rs267606908, ExAC no frequency). This variant has been reported to segregate with disease in two large families affected with hypertrophic cardiomyopathy (HCM) (PMID: 12081993, 15528230), and has also been reported in several unrelated individuals affected with HCM (PMID: 24704860, 24510615). ClinVar contains an entry for this variant (Variation ID: 14125). One experimental study has shown that this variant enhances myosin velocity-generating capacity in an in vitro motility assay (PMID: 15528230). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000617405 SCV000736390 pathogenic Cardiovascular phenotype 2019-04-30 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Good segregation with disease (lod 1.5-3 = 5-9 meioses);Other strong data supporting pathogenic classification
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000158569 SCV000861540 pathogenic not provided 2018-05-25 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000762923 SCV000893341 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
Integrated Genetics/Laboratory Corporation of America RCV000035817 SCV000917840 pathogenic Primary familial hypertrophic cardiomyopathy 2018-05-03 criteria provided, single submitter clinical testing Variant summary: MYH7 c.2717A>G (p.Asp906Gly) results in a non-conservative amino acid change located in the Myosin tail domain (IPR002928) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 247498 control chromosomes (gnomAD and publications). The variant, c.2717A>G, has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (including apical hypertrophy) but also in unaffected individuals and is considered to have reduced penetrance (Ho_2002, Arad_2005, Alpert_2005, Miller_2012, Kapplinger_2014). This variant was also reported in compound heterozygosity with MYBPC3 c.3226_3227insT (p.Asp1076fsX6) and MYH7 c.2722C>G (p.Leu908Val)(Alpert_MYH7_AJPHCP_2005 and internal specimen). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Alpert_2005). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000015185 SCV000993573 pathogenic Familial hypertrophic cardiomyopathy 1 2019-08-22 criteria provided, single submitter research
Color RCV001181317 SCV001346438 pathogenic Cardiomyopathy 2019-05-24 criteria provided, single submitter clinical testing
OMIM RCV000015185 SCV000035442 pathogenic Familial hypertrophic cardiomyopathy 1 2005-11-01 no assertion criteria provided literature only
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000158569 SCV000280333 pathogenic not provided 2012-01-16 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. MYH7 p.Asp906Gly (c.2717A>G) Given the strong case data, strong segregation data, and absence in controls and the general population (reviewed below) we consider this variant very likely disease causing. The variant has been seen in at least 9 unrelated cases of HCM (not including this patient's family). There is strong segregation data. The Seidmans’ group included a kindred with this variant in a study on diastolic dysfunction in HCM (Ho et al 2002). Of 22 carriers studied, 9 had HCM. Alpert et al (2005) reported a family with this variant with 3 of 13 carriers having HCM. Two siblings from this family married two siblings from another family with HCM and a different MYH7 variant. Two offspring carried both variants and both had HCM. The Seidman group later reported a patient with apical HCM and this variant. His brother died suddenly and had evidence of HCM on autopsy (Arad et al 2005). This appears to be a different family than reported in Ho et al (2002). Ackerman's group observed the variant in 4 patients in their cohort of 1053 unrelated patients with HCM who underwent DHLPC-based analysis of 9 sarcomere genes at Mayo (Bos et al 2014). Those cases are presumably redundant with those in another paper by Ackerman’s group that included 5 HCM patients seen at Mayo or tested Transgenomics (Kapplinger et al 2014). McKenna’s group included a patient with HCM and this variant from their UK cohort in a paper on developmental structural differences in HCM (Captur et al 2014). Per their ClinVar submission, LMM considers the variant pathogenic (SCV000059468). The submission does not include any internal case data. 2 additional entries in ClinVar (OMIM and GeneDx) consider this variant pathogenic. In silico analysis with PolyPhen-2 predicts the variant to be benign (HumVar score 0.375). Mutationtaster predicts it to be disease causing. The aspartate at codon 906 is not completely conserved across species. Other variants have been reported in association with disease at this codon (p.Asp906Asn (per ClinVar, LMM considers this of uncertain significance (SCV000059466, last reviewed by LMM in 2010)) and nearby codons (p.Asp900Gly, p.Gln907Lys, p.Leu908Val, p.Ile909Val). In total the variant has not been seen in ~6700 published controls and individuals from publicly available population datasets. There is no variation at codon 906 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of October 3rd, 2014). Additionally, there is no variation at this codon in the ExAC dataset, which contains sequence data from ~65,000 individuals of varying ancestries from various exome sequencing cohorts (as of Feb 26, 2015). The variant is listed in dbSNP (rs267606908) with the only submission being disease-related (as of October 3rd, 2014). There is also no variation at this codon listed 1000 genomes (as of October 3rd, 2014). The variant was not observed in the following published control samples: 200 (Bos et al 2014).

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