ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs267606908
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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen 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, Mass General Brigham 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 2020-09-01 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (gnomAD); A functional study demonstrated that this missense variant caused myosin to move actin at an increased velocity compared to control (Alpert et al., 2005); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported as pathogenic in ClinVar by the ClinGen Inherited Cardiomyopathy Expert Panel (SCV000564437.2; ClinVar); This variant is associated with the following publications: (PMID: 28166811, 27532257, 28606303, 24704860, 29300372, 15528230, 28481356, 29203298, 23054336, 12081993, 16267253, 24510615, 26914223, 27247418, 21310275, 28193612, 28241245, 31006259, 32894683, 33087929)
Blueprint Genetics RCV000035817 SCV000264085 pathogenic Primary familial hypertrophic cardiomyopathy 2015-11-10 criteria provided, single submitter clinical testing
Invitae RCV000469895 SCV000546214 pathogenic Hypertrophic cardiomyopathy 2024-01-10 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 906 of the MYH7 protein (p.Asp906Gly). This variant is present in population databases (rs267606908, gnomAD 0.0009%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (HCM) (PMID: 12081993, 15528230, 24510615, 24704860). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14125). 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: 15528230). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000617405 SCV000736390 pathogenic Cardiovascular phenotype 2022-05-02 criteria provided, single submitter clinical testing The p.D906G pathogenic mutation (also known as c.2717A>G), located in coding exon 21 of the MYH7 gene, results from an A to G substitution at nucleotide position 2717. The aspartic acid at codon 906 is replaced by glycine, an amino acid with similar properties. 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 alteration has been identified in a number of hypertrophic cardiomyopathy (HCM) cohorts and is reported to co-segregate with disease in two families, although a second segregating MYH7 alteration was noted in one family (Ho CY et al. Circulation. 2002;105:2992-7; Alpert NR et al. Am. J. Physiol. Heart Circ. Physiol. 2005;288:H1097-102; Arad M et al. Circulation. 2005;112:2805-11; Miller EM et al. J Genet Couns. 2013;22:258-67; Kapplinger JD et al. J Cardiovasc Transl Res. 2014;7:347-61; Lopes LR et al. Heart. 2015;101:294-301; Walsh R et al. Genet. Med. 2017;19:192-203; Weissler-Snir A et al. Circ Cardiovasc Imaging. 2017;10:e005311). One in vitro functional assay using isolated myosin from p.D906G carriers found increased velocity of actin translocation compared to wild-type, and a second functional assay suggested that the p.D906G mutation weakens an interaction between the S1 and S2 domains of MYH7 that sequesters myosin heads and prevents them from interacting with actin (Alpert NR et al. Am. J. Physiol. Heart Circ. Physiol. 2005;288:H1097-102; Nag S et al. Nat. Struct. Mol. Biol. 2017;24:525-533). 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.
Eurofins Ntd Llc (ga) RCV000158569 SCV000861540 pathogenic not provided 2018-05-25 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000762923 SCV000893341 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 2021-10-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000035817 SCV000917840 pathogenic Primary familial hypertrophic cardiomyopathy 2021-11-21 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. Three 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 252714 control chromosomes. c.2717A>G, has been reported in the literature in to co-segregate with disease multiple individuals affected with Hypertrophic Cardiomyopathy (including apical hypertrophy) but also in unaffected individuals and is considered to have reduced penetrance (example, 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). Compound heterozygotes (2 variants in MYH7, 2 variants in MYBPC3, or 1 variant each in MYH7 and MYBPC3) are known to be associated with more severe prognosis (example, Alpert_2005). 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 where it increased velocity of actin translocation compared to wild-type (example, Alpert_2005). Multiple clinical diagnostic laboratories and an expert panel (ClinGen Cardiomyopathy Variant Curation Expert Panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters 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 Hypertrophic cardiomyopathy 1 2019-08-22 criteria provided, single submitter research
Color Diagnostics, LLC DBA Color Health RCV001181317 SCV001346438 pathogenic Cardiomyopathy 2023-04-28 criteria provided, single submitter clinical testing This missense variant replaces aspartic acid with glycine at codon 906 of the MYH7 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant is found within a highly conserved region of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). An in vitro functional motility assay has shown that this variant enhances myosin velocity-generating capacity (PMID: 15528230). Another in-vitro functional study has shown that this variant decreased affinity to the S1 binding domain (PMID: 28481356). This variant has been reported in over 20 individuals affected with hypertrophic cardiomyopathy (PMID: 16267253, 24510615, 24704860, 27532257, 33495597, 35026164). It has been shown that this variant segregates with disease in over 10 affected individuals from multiple families (PMID: 12081993, 15528230). This variant has been identified in 1/251460 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV000158569 SCV001715068 pathogenic not provided 2022-09-21 criteria provided, single submitter clinical testing PP1_strong, PP3, PM1, PM2, PS4
Revvity Omics, Revvity Omics RCV000158569 SCV002017667 pathogenic not provided 2020-11-06 criteria provided, single submitter clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center RCV000158569 SCV002051556 pathogenic not provided 2021-02-04 criteria provided, single submitter clinical testing PS4, PM1, PM2
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV001181317 SCV003838754 pathogenic Cardiomyopathy 2021-06-15 criteria provided, single submitter clinical testing
OMIM RCV000015185 SCV000035442 pathogenic 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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