ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.3286G>T (p.Asp1096Tyr) (rs45478699)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 16
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Cardiomyopathy Variant Curation Expert Panel RCV000758039 SCV000577981 likely benign Cardiomyopathy 2021-03-22 reviewed by expert panel curation The c.3286G>T (p.Asp1096Tyr) variant in MYH7 has been identified in 0.023% (FAF 95% CI; 40/129162) of European chromosomes in gnomAD v2.1.1 (https://gnomad.broadinstitute.org), which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BS1; Kelly 2018 PMID:29300372). Allowing a variant to reach a likely benign classification based on BS1 alone represents a revision of the original ACMG/AMP framework by ClinGen’s Sequence Variant Interpretation Working Group (Tavtigian 2018 PMID: 29300386). Additionally, while computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3), this pathogenic evidence code (PP3) was not considered to be in conflict with a likely benign conclusion given the accuracy of computation prediction tools. In summary, this variant meets criteria to be classified as likely benign for cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PP3, BS1
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000035846 SCV000059497 uncertain significance not specified 2016-09-13 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Asp1096Ty r variant has been previously reported in 3 individuals with DCM and 1 teenager with left ventricular hypertrophy and a family history of DCM (Hershberger 2008, Helms 2014, LMM data). This variant has also been identified in 18/66702 Europe an chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinsti tute.org; dbSNP rs45478699). Aspartic acid (Asp) at position 1096 is highly cons erved in mammals and the change to tyrosine (Tyr) was predicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In summary, while there is some suspicion for a pathogenic role, the clinical si gnificance of the p.Asp1096Tyr variant is uncertain.
GeneDx RCV000656921 SCV000208535 likely benign not provided 2021-04-26 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 23299917, 25163546, 32659924, 22337857, 23403236, 18555187, 27247418, 25031304, 19412328, 26383716, 27688314, 29300372, 28798025, 31737537, 28588093, 32528171, 32880476)
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000201875 SCV000256636 uncertain significance Familial hypertrophic cardiomyopathy 1 2015-07-30 criteria provided, single submitter research The Asp1096Tyr variant in MYH7 has been previously reported by Hershberger et al (2008) in 2 DCM probands. Helms et al (2014) analysed sarcomere transcript and protein levels in septal myectomy and transplant specimens from genotyped HCM patients - one of whome carried this MYH Asp1096Tyr variant. This variant has been reported with an allele frequency of 0.0001 (18/66,720 European non-Finnish alleles and 1/908 'other') in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). The MYH7 Asp1096Tyr variant occurs in a conserved region, and in-silico tools (SIFT, PolyPhen, MutationTaster and CADD) support a damaging role for this variant, however this alone is not strong evidence for pathogenicity. We have identified this variant in 1 HCM proband who presented in her 30's with asymmetric hypertrophy (IVS 21mm) and obstruction. This proband experienced a sudden cardiac death in her 50s. It is noted that this proband also carried a pathogenic MYBPC3 nonsense variant. Based on the limited reports in the literature, and our finding of MYH7 Asp1096Tyr in an isolated HCM case who carried an additional variant which is known to be disease-causing, we have classified this variant as having "uncertain significance". Additional evidence is required to fully establish its pathogenic role.
Invitae RCV000529912 SCV000623693 uncertain significance Hypertrophic cardiomyopathy 2019-10-07 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with tyrosine at codon 1096 of the MYH7 protein (p.Asp1096Tyr). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and tyrosine. This variant is present in population databases (rs45478699, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in individuals affected with cardiomyopathy (PMID: 19412328, 27247418, 25031304, 29300372, 25163446) and left ventricular noncompaction (LVNC) (PMID: 28798025). ClinVar contains an entry for this variant (Variation ID: 42953). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
CSER _CC_NCGL, University of Washington RCV000590886 SCV000700123 likely pathogenic Primary dilated cardiomyopathy 2016-10-01 criteria provided, single submitter research Found in patient having exome sequencing for an unrelated indication. No known history of dilated cardiomyopathy. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review.
Ambry Genetics RCV000620264 SCV000736672 uncertain significance Cardiovascular phenotype 2018-12-30 criteria provided, single submitter clinical testing The p.D1096Y variant (also known as c.3286G>T), located in coding exon 24 of the MYH7 gene, results from a G to T substitution at nucleotide position 3286. The aspartic acid at codon 1096 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration has been detected in dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), left ventricular non-compaction (LVNC), and arrhythmogenic right ventricular cardiomyopathy (ARVC) cohorts; however, in several cases, clinical detail was limited, or it co-occurred with variants in other cardiac-related genes (Hershberger RE et al. Clin Transl Sci. 2008;1:21-6; Helms AS et al. Circ Cardiovasc Genet. 2014;7:434-43; Haas J et al. Eur. Heart J. 2015;36:1123-35a; Miszalski-Jamka K et al. Circ Cardiovasc Genet. 2017;10(4); Orgeron GM et al. J Am Heart Assoc. 2017;6(6)). This variant has also been detected in exome cohorts (Andreasen C et al. Eur. J. Hum. Genet. 2013 Sep;21(9):918-28). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Health, Inc RCV000758039 SCV000913719 uncertain significance Cardiomyopathy 2020-08-27 criteria provided, single submitter clinical testing This missense variant replaces aspartic acid with tyrosine at codon 1096 of the MYH7 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant.This variant has been reported in several individuals affected with cardiomyopathy (PMID: 19412328, 27247418, 25031304, 32659924). This variant has also been identified in 40/282846 chromosomes (40/129122 non-Finnish European chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Although the variant allele frequency is greater than expected for MYH7-related disorders based on prevalence, penetrance and allelic heterogeneity, the available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000656921 SCV001149179 uncertain significance not provided 2019-04-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000491282 SCV001272028 benign Dilated cardiomyopathy 1S 2019-05-21 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Illumina Clinical Services Laboratory,Illumina RCV001114182 SCV001272029 benign Myopathy, distal, 1 2019-05-21 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Illumina Clinical Services Laboratory,Illumina RCV001114183 SCV001272030 uncertain significance Myosin storage myopathy 2019-05-21 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Institute of Human Genetics, University of Leipzig Medical Center RCV000491282 SCV001440771 uncertain significance Dilated cardiomyopathy 1S 2019-01-01 criteria provided, single submitter clinical testing
Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations RCV001265537 SCV001443279 uncertain significance See cases 2020-11-17 criteria provided, single submitter clinical testing We observed a genetic variant c.3286G>T (p.D1096Y) in a male 68-y.o. patient diagnosed with left ventricular non-compaction and heart rhythm disorders. The p.D1096Y variant has a frequency of 1.414e-4 in gnomAD. The variant was detected in a MYH7 gene with z-score of 3.93, therefore intolerant to missense variants. Online in silico tools (PolyPhen2, MutationTaster, SIFT) predict the variant to be deleterious. However, in the absence of family screening results and the data on functional effects, we could only classify the p.D1096Y variant as the variant of uncertain clinical significance.
Erich and Hanna Klessmann Institute for Cardiovascular Research and Development,Heart and Diabetes Center North Rhine-Westphalia RCV000491282 SCV000298099 uncertain significance Dilated cardiomyopathy 1S 2016-05-01 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000656921 SCV001549878 uncertain significance not provided no assertion criteria provided clinical testing The MYH7 p.Asp1096Tyr variant was identified in 4 of 1006 proband chromosomes (frequency: 0.00398) from individuals with dilated cardiomyopathy (DCM) or left ventricular non-compaction (LVNC) and was not identified in 506 control chromosomes from healthy individuals (Hershberger_2008_PMID:19412328; Miszalski-Jamka_2017_PMID:28798025). The variant was identified in dbSNP (ID: rs45478699) and ClinVar (classified as uncertain significance by Invitae, Laboratory for Molecular Medicine, ClinGen Inherited Cardiomyopathy Variant Curation Expert Panel and five other laboratories, and classified as likely pathogenic by CSER_CC_NCGL; University of Washington Medical Center). The variant was identified in control databases in 40 of 282846 chromosomes at a frequency of 0.0001414 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the European (non-Finnish) population in 40 of 129162 chromosomes (freq: 0.00031), but was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other, or South Asian populations. The p.Asp1096 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.